Administration of airborne pathogens in non-human primates.

PURPOSE: Airborne pathogen scan penetrate in human respiratory tract and can cause illness. The use of animal models to predict aerosol deposition and study respiratory disease pathophysiology is therefore important for research and a prerequisite to test and study the mechanism of action of treatment. NHPs are relevant animal species for inhalation studies because of their similarities with humans in terms of anatomical structure, respiratory parameters and immune system. MATERIALS AND METHODS: The aim of this review is to provide an overview of the state of the art of pathogen aerosol studies performed in non-human primates (NHPs). Herein, we present and discuss the deposition of aerosolized bacteria and viruses. In this review, we present important advantages of using NHPs as model for inhalation studies. RESULTS: We demonstrate that deposition in the respiratory tract is not only a function of aerosol size but also the technique of administration influences the biological activity and site of aerosol deposition. Finally, we observe an influence of a region of pathogen deposition in the respiratory tract on the development of the pathophysiological effect in NHPs. CONCLUSION: The wide range of methods used for the delivery of pathogento NHP respiratory airways is associated with varying doses and deposition profiles in the airways.

"To BAL or not to BAL, that is the question": Variations in smoke inhalation injury guidelines from burn units and centres in England, Scotland and Wales.

AIM: To evaluate variations in diagnostic criteria and management recommendations for smoke inhalation injury (SII) amongst the burn networks of England, Scotland, and Wales. METHODS: A descriptive cross-sectional study examining SII guidelines provided by adult burn units and centres in England, Scotland and Wales. RESULTS: All 16 adult burn units and centres responded. Fourteen (87.5 %) had guidelines. Due to sharing of guidelines, ten unique guidelines were assessed. Diagnostic criteria showed variability with no universal criterion shared amongst guidelines. Bronchoscopy was recommended by 90 % of guidelines, but the timing varied. The use of bronchoscopic scoring systems was recommended by four guidelines. Bronchoalveolar lavage (BAL) was recommended by four, with considerable variation in frequency and choice of lavage fluid. All guidelines advised at least one nebulised agent: heparin (n = 8); N-acetyl cysteine (NAC) (n = 8); or salbutamol (n = 8). All guidelines included advice on carbon monoxide poisoning; however, carboxyhaemoglobin (COHb) cut-off levels for treatment varied (5 % [n-4], 10 % [n = 3], 15 % [n = 1]). All recommended high-flow oxygen. Seven (70 %) guidelines offered guidance on cyanide poisoning. Reduced/altered consciousness was the only consistent diagnostic criterion. Five (50 %) guidelines provided intubation guidance, emphasising the role of a 'senior clinician' as the intubator. Ventilatory guidance appeared in eight guidelines, focusing on lung protective ventilation (n = 8); oxygenation goals (n = 3); and permissive hypercapnia (n = 3). Within lung-protective ventilation, advice on tidal volume (6, or 6-8 ml/kg) and plateau pressures (>30 cmH2O) were presented most commonly (n = 7). CONCLUSION: This study has outlined the substantial variations in guidance for the management of SII. The results underscore the need for a national guideline outlining a standardised approach to the diagnosis and management of SII, within the limitations of the current evidence.

Dependence of aerosol-borne influenza A virus infectivity on relative humidity and aerosol composition.

We describe a novel biosafety aerosol chamber equipped with state-of-the-art instrumentation for bubble-bursting aerosol generation, size distribution measurement, and condensation-growth collection to minimize sampling artifacts when measuring virus infectivity in aerosol particles. Using this facility, we investigated the effect of relative humidity (RH) in very clean air without trace gases (except ∼400 ppm CO2) on the preservation of influenza A virus (IAV) infectivity in saline aerosol particles. We characterized infectivity in terms of 99%-inactivation time, t 99, a metric we consider most relevant to airborne virus transmission. The viruses remained infectious for a long time, namely t 99 > 5 h, if RH < 30% and the particles effloresced. Under intermediate conditions of humidity (40% < RH < 70%), the loss of infectivity was the most rapid (t 99 ≈ 15-20 min, and up to t 99 ≈ 35 min at 95% RH). This is more than an order of magnitude faster than suggested by many previous studies of aerosol-borne IAV, possibly due to the use of matrices containing organic molecules, such as proteins, with protective effects for the virus. We tested this hypothesis by adding sucrose to our aerosolization medium and, indeed, observed protection of IAV at intermediate RH (55%). Interestingly, the t 99 of our measurements are also systematically lower than those in 1-µL droplet measurements of organic-free saline solutions, which cannot be explained by particle size effects alone.

[Recommendations for Reducing the Environmental Impact of Inhalers in Portugal: Consensus Document]. / Recomendações para a Redução do Impacto Ambiental dos Inaladores em Portugal: Documento de Consenso.

This consensus document addresses the reduction of the environmental impact of inhalers in Portugal. It was prepared by the Portuguese Council for Health and the Environment and the societies representing the specialties that account for these drugs' largest volume of prescriptions, namely the Portuguese Society of Pulmonology, the Portuguese Society of Allergology and Clinical Immunology, the Portuguese Society of Pediatrics, the Portuguese Society of Internal Medicine, the Portuguese Association of General and Family Medicine and also a patient association, the Respira Association. The document acknowledges the significant impact of pressurized metered-dose inhalers on greenhouse gas emissions and highlights the need to transition to more sustainable alternatives. The carbon footprint of pressurized metered-dose inhalers and dry powder inhalers in Portugal was calculated, and the level of awareness among prescribing physicians on this topic was also estimated. Finally, recommendations were developed to accelerate the reduction of the ecological footprint of inhalers.

Este documento de consenso aborda a redução do impacto ambiental dos inaladores em Portugal. Foi elaborado pelo Conselho Português para a Saúde e Ambiente e pelas sociedades que representam as especialidades com maior volume de prescrição destes medicamentos, nomeadamente a Sociedade Portuguesa de Pneumologia, a Sociedade Portuguesa de Alergologia e Imunologia Clínica, a Sociedade Portuguesa de Pediatria, a Sociedade Portuguesa de Medicina Interna e a Associação Portuguesa de Medicina Geral e Familiar em conjunto com uma associação de doentes, a Associação Respira. Reconhece-se o impacto significativo dos inaladores pressurizados doseáveis nas emissões de gases com efeito de estufa e a necessidade de transição para alternativas mais sustentáveis. Calculou-se a pegada de carbono dos inaladores pressurizados doseáveis e dos inaladores de pó seco em Portugal e estimou-se o nível de literacia dos médicos prescritores relativamente a este tema. Finalmente, foram elaboradas recomendações com o objetivo de acelerar a redução da pegada ecológica dos inaladores.

Dos and don'ts to optimize transnasal aerosol drug delivery in clinical practice.

INTRODUCTION: Transnasal aerosol drug delivery has become widely accepted for treating acutely ill infants, children, and adults. More recently aerosol administration to wider populations receiving high and low-flow nasal oxygen has become common practice. AREAS COVERED: Skepticism of insufficient aerosol delivery to the lungs has been tempered by multiple in vitro explorations of variables to optimize delivery efficiency. Additionally, clinical studies demonstrated comparable clinical responses to orally inhaled aerosols. This paper provides essential clinical guidance on how to improve transnasal aerosol delivery based on device-, settings-, and drug-related optimization to serve as a resource for educational initiatives and quality enhancement endeavors at healthcare institutions. EXPERT OPINION: Transnasal aerosol delivery is proliferating worldwide, but indiscriminate use of excessive-high flows, poor selection and placement of aerosol devices and circuits can greatly reduce aerosol delivery and efficacy, potentially compromising treatment to acute and critically ill patients. Attention to these details can improve inhaled dose by an order of magnitude, making the difference between effective treatment and the progression to more invasive ventilatory support, with greater inherent risk and cost. These revelations have prompted specific recommendations for optimal delivery, driving advancements in aerosol generators, formulations, and future device designs to administer aerosols and maximize treatment effectiveness.

Are the Reference Values for the Provocative Concentration of Methacholine Appropriate for Children?

Background: Preliminary data in a randomly selected pediatric cohort study in 8-year-olds suggested a rate of positivity to a methacholine challenge test that was unexpectedly high, roughly 30%. The current recommendation for a negative methacholine test is a 20% decrease in the forced expiratory volume in one second at a dose greater than 400 µg. This was derived from studies in adults using the obsolete English Wright nebulizer. One explanation for the high incidence of positivity in the study in 8-year-olds could be that children deposit more methacholine on a µg/kg basis than adults, due to differences in their breathing patterns. The purpose of this study was to determine if pediatric breathing patterns could result in a higher dose of methacholine depositing in the lungs of children based on µg/kg body weight compared with adults. Methods: An AeroEclipse Breath Actuated nebulizer delivered methacholine aerosol, generated from a 16 mg/mL solution, for one minute, using age-appropriate breathing patterns for a 70 kg adult and a 30 and 50 kg child produced by a breathing simulator. Predicted lung deposition was calculated from the collected dose of methacholine on a filter placed at the nebulizer outport, multiplied by the fraction of the aerosol mass contained in particles ≤5 µm. The dose of methacholine on the inspiratory filter was assayed by high performance liquid chromatography (HPLC). Particle size was measured using laser diffraction technology. Results: The mean (95% confidence intervals) predicted pulmonary dose of methacholine was 46.1 (45.4, 46.8), 48.6 (45.3, 51.9), and 36.1 (34.2, 37.9) µg/kg body weight for the 30 kg child, 50 kg child, and 70 kg adult, respectively. Conclusions: On a µg/kg body weight, the predicted pulmonary dose of methacholine was greater with the pediatric breathing patterns than with the adult pattern.

A Pediatric Bench Model of Continuous Albuterol Delivery Using Heliox.

BACKGROUND: The optimal setup for continuously administering albuterol with heliox remains unclear, especially for pediatric patients. This study aimed to evaluate the efficiency of continuous albuterol delivery with heliox using different nebulizer setups in a pediatric model. METHODS: A pediatric manikin with simulated spontaneous breathing was used to receive continuous albuterol (20 mg/h) with heliox (80/20) in 3 setups: (1) The MiniHEART nebulizer, driven by oxygen at 3 L/min, was attached to a Y-piece, linking to a non-rebreather mask and a valved reservoir with 11 L/min heliox; (2) a vibrating mesh nebulizer (VMN) placed at the humidifier inlet of high-flow nasal cannula (HFNC) with 11 L/min heliox and the manikin's mouth sealed; and (3) a VMN placed between a valved reservoir with 11 L/min heliox and a non-rebreather mask. Both tight-fitting and loose-fitting mask configurations were tested in the setup with vibrating mesh nebulizer and mask. Heliox of 70/30 was tested with a VMN and a loose-fitting mask. Albuterol was delivered continuously to the nebulizer via an infusion pump at 8 mL (20 mg)/h for each 20-min run and each experiment was repeated five times. A collecting filter placed between the manikin's trachea and lung model was removed after each run, and the drug was eluted and assayed via ultraviolet spectrophotometry (276 nm). RESULTS: During continuous albuterol nebulization using heliox, the VMN either in line with HFNC or with a tight-fitting mask achieved the highest and similar inhaled dose (8.5 ± 0.4 vs 8.8 ± 0.7%, P = .35), while the MiniHEART nebulizer yielded the lowest aerosol deposition (1.5 ± 0.2%). The inhaled dose was lower with the loose-fitting mask than with the tight-fitting mask (5.9 ± 0.9 vs 8.8 ± 0.7%, P=.009), and heliox of 80/20 delivered a higher inhaled dose than heliox of 70/30 (5.9 ± 0.9 vs 3.9 ± 0.4%, P=.009). CONCLUSIONS: When administering continuous albuterol with heliox in a pediatric model, utilizing a VMN in line with HFNC during closed-mouth breathing yielded a higher inhaled dose compared to both the MiniHEART nebulizer and VMN with a loose-fitting mask.

External Jet Nebulization and Measured Ventilator Performance.

BACKGROUND: During invasive ventilation, external flow jet nebulization results in increases in displayed exhaled tidal volumes (VT). We hypothesized that the magnitude of the increase is inaccurate. An ASL 5000 simulator measured ventilatory parameters over a wide range of adult settings: actual VT, peak inspiratory pressure (PIP), and time to minimum pressure. METHODS: Ventilators with internal and external flow sensors were tested by using a variety of volume and pressure control modes (the target VT was 420 mL). Patient conditions (normal, COPD, ARDS) defined on the ASL 5000 were assessed at baseline and with 3.5 or 8 L/min of added external flow. Patient-triggering was assessed by reducing muscle effort to the level that resulted in backup ventilation and by changing ventilator sensitivity to the point of auto-triggering. RESULTS: Results are reported as percentage change from baseline after addition of 3.5 or 8 L/min external flow. For ventilators with internal flow sensors, changes in displayed exhaled VT ranged from 10% to 118%, however, when using volume control, actual increases in actual VT and PIP were only 4%-21% (P = .063, .031) and 6%-24% (P = .25, .031), respectively. Changes in actual VT correlated closely with changes in PIP (P < .001; R2 = 0.68). For pressure control, actual VT decreased by 3%-5% (P = .031) and 4%-9% (P = .031) with 3.5 and 8 L/min respectively, PIP was unchanged. With external flow sensors at the distal Y-piece junction, volume and pressure changes were statistically insignificant. The time to minimum pressure increased at most by 8% (P = .02) across all modes and ventilators. The effects on muscle pressure were minimal (∼1 cm H2O), and ventilator sensitivity effects were nearly undetectable. CONCLUSIONS: External flow jet nebulization resulted in much smaller changes in volume than indicated by the ventilator display. Statistically significant effects were confined primarily to machines with internal flow sensors. Differences approached the manufacturer-reported variation in ventilator baseline performance. During nebulizer therapy, effects on VT can be estimated at the bedside by monitoring PIP.

New Generation Nebulizers.

Standard nebulizers are intended for general purpose use and typically are continuously operated jet or ultrasonic nebulizers. Evolutionary developments such as breath-enhanced and breath-triggered devices have improved delivery efficiency and ease of use, yet are still suitable for delivery of nebulized medications approved in this category. However, recent developments of vibrating membrane or mesh nebulizers have given rise to a significant increase in delivery efficiency requiring reformulation of former drug products or development of new formulations to match the enhanced delivery characteristics of these new devices. In addition, the electronic nature of the new devices enables tailoring to specific applications and patient groups, such as guiding or facilitating optimal breathing and improving adherence to the therapeutic regimen. Addressing these patient needs leads to new nebulization technologies being embedded in devices with fundamentally distinct functionality, modes of operation and patient interfaces. Therefore, new generation nebulizers can no longer be regarded as one category with fairly similar performance characteristics but must be clinically tested and approved as drug/device combinations together with the specific drug formulation, similar to the approval of pressurized metered-dose inhalers and dry powder inhalers. From a regulatory viewpoint, it is required that drug and device are associated with each other as combinations by clear, mutually conforming labels or, even more desirably, by distinct container-closure systems (closed system nebulizer).

Estimating Tiotropium Wasted Doses After Adding Revefenacin to an Inpatient Formulary: A Single-Center Cross-Sectional Study.

Introduction: Revefenacin is a once-daily nebulized long-acting muscarinic antagonist (LAMA). Revefenacin is supplied as single-use nebulized vials, which may be preferable and less costly for hospital and health-system pharmacies to dispense versus multidose tiotropium inhalers. Estimates of LAMA multidose inhaler wasted doses remains unknown. Methods: This was a single-center descriptive cross-sectional study conducted between January 1 2021 and December 31 2021. Adult patients 18 years and older admitted to a 500-bed academic medical center in the southern United States and were ordered multidose tiotropium packages or single-use revefenacin vials during the study period were included. Results: Among 602 inpatients, there were 705 LAMA orders: 541 tiotropium (76.7%) and 164 revefenacin (23.3%). Four hundred ninety-five tiotropium orders (91.5%) wasted between 20% and 90% of multidose packages. Approximately $24,000 tiotropium doses were wasted versus single-use revefenacin vials. Conclusion: Multidose inhalers of tiotropium dispensed to hospitalized patients contributed to wasted doses compared to nebulized single-use revefenacin vials. Opportunities exist to minimize wasted doses of multidose long-acting inhalers dispensed to hospitalized patients.

Filling the gaps in the evaluation and selection of mobile health technologies in respiratory medicine.

INTRODUCTION: Mobile health (mHealth) technology in respiratory medicine is a fast-growing and promising digital technology that is popular among patients and healthcare providers (HCPs). They provide reminders and step-by-step instructions for the correct inhalation technique, monitor patients' adherence to treatment, and facilitate communication between patients and HCPs. AREAS COVERED: While numerous mHealth apps have been developed over the years, most applications do not have supporting evidence. Selecting the best mHealth app in respiratory medicine is challenging due to limited studies carrying out mHealth app selection. Although mHealth technologies play an important part in the future of respiratory medicine, there is no single guide on the evaluation and selection of mHealth technologies for patients with pulmonary diseases. This paper aims to provide an overview of mHealth technologies, particularly emphasizing digital inhalers and standalone applications used in asthma. Additionally, it offers insights into the evaluation, selection, and pertinent considerations surrounding mHealth applications in respiratory medicine. EXPERT OPINION: Evaluating mHealth apps will take time, resources, and collaboration between stakeholders such as governmental regulatory bodies, subject-matter experts, and industry representatives. Filling the gaps in the evaluation and selection of the mHealth app will improve clinical decision-making, personalized treatments, self-management and disease monitoring in respiratory medicine.

Pulmonologist Education of the Teach-to-Goal Inhaler Technique for Those With Asthma and COPD.

BACKGROUND: Inhaler education for patients with asthma and patients with COPD is typically provided by non-pulmonologists. We studied inhaler education by pulmonologists to determine changes in clinical outcomes and inhaler use. METHODS: This was a retrospective study of 296 subjects diagnosed with asthma, COPD, or both that evaluated use of inhaler technique education and its impact on (1) inhaler/dosage change consisting of dosage change in the same class of inhaler and/or change in number of inhalers, (2) forced expiratory volume in one second/forced vital capacity (FEV1/FVC%), (3) disease symptom control, (4) out-patient visits, (5) urgent care visits (6) emergency department visits, and (7) hospital admissions. One group received inhaler technique education by a pulmonologist while the other group did not. RESULTS: The pulmonologist inhaler technique-educated group had significantly decreased relative risk for inhaler/dosage increase (relative risk 0.57 [95% CI 0.34-0.96], P = .03) and significantly increased odds for symptom control (odds ratio 2.15 [95% CI 1.24-3.74], P = .01) at 1-y follow-up as compared to the no education group. No differences occurred for FEV1/FVC%, out-patient visits, urgent care visits, emergency department visits, and hospital admissions. CONCLUSIONS: Pulmonologist education of inhaler technique for patients with asthma and patients with COPD was associated with decreased relative risk for inhaler/dosage increase and increased odds for symptom control. We recommend pulmonologists provide education of inhaler technique to patients with asthma and patients with COPD and not rely on non-pulmonologist education alone. Prospective research is needed to confirm the importance of proper inhaler techniques.

Validation of an Inhaled Therapy Beliefs Questionnaire in Patients with Chronic Obstructive Pulmonary Disease.

Background: To carry out a validation questionnaire that assesses beliefs about inhaled treatments in patients with chronic obstructive pulmonary disease (COPD), as knowing patients' beliefs could help to improve medication adherence and health outcomes. Methods: We evaluated data from 260 COPD patients from electronic medical record databases from five primary healthcare centers, in a descriptive, cross-sectional study with a sample size calculated for a 10-item questionnaire, with an estimated Cronbach's alpha of 0.70 and a 95% confidence level. Study participants were selected via systematic random sampling. Variables: Ten-item Inhaled Therapy Beliefs Questionnaire, CCTI-Questionnaire v.2.0, time for completion, age, sex, educational level, spirometry severity (GOLD criteria), exacerbations (previous year), characteristics of inhaled treatment, and smoking habit. A two-year follow-up in a subsample of 77 patients from one health center was utilized. The Morisky-Green test, pharmacy dispensing data, test-retest (kappa coefficient), and an exploratory analysis of the adherence-belief relationship (ji-squared) were measured. Results: The 10-item questionnaire showed good viability (3 min completion time) when performed face-to-face or telephonically; its psychometric properties were acceptable, with an internal consistency (Cronbach's alpha) score of 0.613. Three factors explained 47.58% of the total variance (p < 0.0001): use (factor 1), effects (factor 2), and objectives (factor 3) of inhalers. The two-year follow-up ultimately considered 58 out of the 77 patients (10 deceased, 4 unlocated, 2 mistakes, 2 no inhaled treatment, and 1 withdrawal). Non-adherence was 48.3% in terms of the Morisky-Green test; 31% in terms of pharmacy dispensing data; and 40.4% considering both methods. There was low test-retest reliability, indicated by items 4, 8, and 9 of the CCTI-Questionnaire (Kappa = 0.4, 0.26, and 0.34; p-value < 0.0001, 0.008, and 0.001, respectively). There was mild correlation between beliefs and adherence. Conclusions: The ten-item CCTI-Questionnaire v.2.0 demonstrated acceptable psychometric properties regarding feasibility, reliability, and content validity.

Comparison of the Application of Vibrating Mesh Nebulizer and Jet Nebulizer in Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-analysis.

Objective: To comparison of the application of Vibrating Mesh Nebulizer and Jet Nebulizer in chronic obstructive pulmonary disease (COPD). Research Methods: This systematic review and meta-analysis was conducted following the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statements. The primary outcome measures analyzed included: The amount of inhaler in the urine sample at 30 minutes after inhalation therapy (USAL0.5), The total amount of inhaler in urine sample within 24 hours (USAL24), Aerosol emitted, Forced expiratory volume in 1 second (FEV1), Forced vital capacity (FVC). Results: Ten studies were included with a total of 314 study participants, including 157 subjects in the VMN group and 157 subjects in the JN group. The data analysis results of USAL0.5, MD (1.88 [95% CI, 0.95 to 2.81], P = 0.000), showed a statistically significant difference. USAL24, MD (1.61 [95% CI, 1.14 to 2.09], P = 0.000), showed a statistically significant difference. The results of aerosol emitted showed a statistically significant difference in MD (3.44 [95% CI, 2.84 to 4.04], P = 0.000). The results of FEV1 showed MD (0.05 [95% CI, -0.24 to 0.35], P=0.716), the results were not statistically significant. The results of FVC showed MD (0.11 [95% CI, -0.18 to 0.41], P=0.459), the results were not statistically significant. It suggests that VMN is better than JN and provides higher aerosols, but there is no difference in improving lung function between them. Conclusion: VMN is significantly better than JN in terms of drug delivery and utilization in the treatment of patients with COPD. However, in the future use of nebulizers, it is important to select a matching nebulizer based on a combination of factors such as mechanism of action of the nebulizer, disease type and comorbidities, ventilation strategies and modes, drug formulations, as well as cost-effectiveness, in order to achieve the ideal treatment of COPD.

Surfactant therapy using vibrating-mesh nebulizers in adults with COVID-19-induced ARDS: A case series.

Coronavirus adult respiratory distress syndrome, characterized by decreased surfactant due to lysis of type II pneumocytes and hyaline membrane formation, contributes to severe hypoxemia. The administration of surfactant via high-flow nasal cannula (HFNC) may positively affect lung structure and function in this context. In this study, we report on five clinical cases, encompassing patients aged 40-60 years of both sexes, who tested positive for coronavirus disease 2019 via real-time polymerase chain reaction and exhibited significant pulmonary compromise with elevated inflammatory biomarkers. These patients were treated with aerosol therapy using surfactant delivered through vibrating-mesh nebulizers alongside HFNC. Of these patients, four demonstrated positive responses to the treatment, suggesting that aerosol therapy with surfactant through vibrating-mesh nebulizers could be a viable rescue therapy in adults receiving HFNC oxygen therapy for hypoxemic respiratory failure caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Unfortunately, one patient had a negative outcome and succumbed. The findings from these cases indicate that the use of aerosol therapy with vibrating-mesh nebulizers as rescue therapy might offer an alternative approach for managing adults with hypoxemic respiratory failure due to SARS-CoV-2, as evidenced by the positive outcomes in four out of the five cases presented.

Nano-Formulations for Pulmonary Delivery: Past, Present, and Future Perspectives.

With the development of nanotechnology and confronting the problems of traditional pharmaceutical formulations in treating lung diseases, inhalable nano-formulations have attracted interest. Inhalable nano-formulations for treating lung diseases allow for precise pulmonary drug delivery, overcoming physiological barriers, improving aerosol lung deposition rates, and increasing drug bioavailability. They are expected to solve the difficulties faced in treating lung diseases. However, limited success has been recorded in the industrialization translation of inhalable nano-formulations. Only one relevant product has been approved by the FDA to date, suggesting that there are still many issues to be resolved in the clinical application of inhalable nano-formulations. These systems are characterized by a dependence on inhalation devices, while the adaptability of device formulation is still inconclusive, which is the most important issue impeding translational research. In this review, we categorized various inhalable nano-formulations, summarized the advantages of inhalable nano-formulations over conventional inhalation formulations, and listed the inhalable nano-formulations undergoing clinical studies. We focused on the influence of inhalation devices on nano-formulations and analyzed their adaptability. After extensive analysis of the drug delivery mechanisms, technical processes, and limitations of different inhalation devices, we concluded that vibrating mesh nebulizers might be most suitable for delivering inhalable nano-formulations, and related examples were introduced to validate our view. Finally, we presented the challenges and outlook for future development. We anticipate providing an informative reference for the field.

Nebulisation of Paclitaxel, Sotatercept and Iloprost for pulmonary hypertension for lung cancer. From In vitro to In vivo.

Background: Pulmonary hypertension is common symptom among several diseases. The consequences are severe for several organs. Pulmonary hypertension is usually under-diagnosed and the main symptom observed is dyspnea with or without exercise. Currently we have several treatment modalities administered orally, via inhalation, intravenously and subcutaneously. In advanced disease then heart or lung transplantation is considered. The objective of the study was to investigate the optimum method of aerosol production for the drugs: iloprost, paclitaxel and the novel sotatercept. Materials and Methods: In our experiment we used the drugs iloprost, paclitaxel and the novel sotatercept, in an experimental concept of nebulization. We performed nebulization experiments with 3 jet nebulizers and 3 ultrasound nebulizers with different combinations of residual cup designs, and residual cup loadings in order to identify which combination produces droplets of less than 5µm in mass median aerodynamic diameter. Results: We concluded that paclitaxel cannot produce small droplets and is also still very greasy and possible dangerous for alveoli. However; iloprost vs sotatercept had smaller droplet size formation at both inhaled technologies (1.37<2.23 and 1.92<3.11, jet and ultrasound respectively). Moreover; residual cup designs C and G create the smallest droplet size in both iloprost and sotatercept. There was no difference for the droplet formation between the facemask and cone mouthpieces. Discussion: Iloprost and sotatercept can be administered as aerosol in any type of nebulisation system and they are both efficient with the residual cups loaded with small doses of the drug (2.08 and 2.12 accordingly).

Aerosol delivery and spatiotemporal tissue distribution of hydroxychloroquine in rat lung.

Inhalation enables the delivery of drugs directly to the lung, increasing the retention for prolonged exposure and maximizing the therapeutic index. However, the differential regional lung exposure kinetics and systemic pharmacokinetics are not fully known, and their estimation is critical for pulmonary drug delivery. The study evaluates the pharmacokinetics of hydroxychloroquine in different regions of the respiratory tract for multiple routes of administration. We also evaluated the influence of different inhaled formulations on systemic and lung pharmacokinetics by identifying suitable nebulizers followed by early characterization of emitted aerosol physicochemical properties. The salt- and freebase-based formulations required different nebulizers and generated aerosol with different physicochemical properties. An administration of hydroxychloroquine by different routes resulted in varied systemic and lung pharmacokinetics, with oral administration resulting in low tissue concentrations in all regions of the respiratory tract. A nose-only inhalation exposure resulted in higher and sustained lung concentrations of hydroxychloroquine with a lung parenchyma-to-blood ratio of 386 after 1440 min post-exposure. The concentrations of hydroxychloroquine in different regions of the respiratory tract (i.e., nasal epithelium, larynx, trachea, bronchi, and lung parenchyma) varied over time, indicating different retention kinetics. The spatiotemporal distribution of hydroxychloroquine in the lung is different due to the heterogeneity of cell types, varying blood perfusion rate, clearance mechanisms, and deposition of inhaled aerosol along the respiratory tract. In addition to highlighting the varied lung physiology, these results demonstrate the ability of the lung to retain increased levels of inhaled lysosomotropic drugs. Such findings are critical for the development of future inhalation-based therapeutics, aiming to optimize target site exposure, enable precision medicine, and ultimately enhance clinical outcomes.

Individualized aerosol medicine: Integrating device into the patient.

Pulmonary drug delivery is complex due to several challenges including disease-, patient-, and clinicians-related factors. Although many inhaled medications are available in aerosol medicine, delivering aerosolized medications to patients requires effective disease management. There is a large gap in the knowledge of clinicians who select and provide instructions for the correct use of aerosol devices. Since improper device selection, incorrect inhaler technique, and poor patient adherence to prescribed medications may result in inadequate disease control, individualized aerosol medicine is essential for effective disease management and control. The components of individualized aerosol medicine include: (1) Selecting the right device, (2) Selecting the right interface, (3) Educating the patient effectively, and (4) Increasing patient adherence to therapy. This paper reviews each of these components and provides recommendations to integrate the device and interface into the patient for better clinical outcomes.