Good Practices for the Laboratory Performance Testing of Aqueous Oral Inhaled Products (OIPs): an Assessment from the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS).

Multiple sources must be consulted to determine the most appropriate procedures for the laboratory-based performance evaluation of aqueous oral inhaled products (OIPs) for the primary measures, dose uniformity/delivery, and aerodynamic particle (droplet) size distribution (APSD). These sources have been developed at different times, mainly in Europe and North America, during the past 25 years by diverse organizations, including pharmacopeial chapter/monograph development committees, regulatory agencies, and national and international standards bodies. As a result, there is a lack of consistency across all the recommendations, with the potential to cause confusion to those developing performance test methods. We have reviewed key methodological aspects of source guidance documents identified by a survey of the pertinent literature and evaluated the underlying evidence supporting their recommendations for the evaluation of these performance measures. We have also subsequently developed a consistent series of solutions to guide those faced with the various associated challenges when developing OIP performance testing methods for oral aqueous inhaled products.

Tiotropium in chronic obstructive pulmonary disease - a review of clinical development.

BACKGROUND: Bronchodilators are the mainstay of pharmacological treatment in chronic obstructive pulmonary disease (COPD), and long-acting muscarinic antagonist (LAMA) monotherapy is recommended as initial treatment for Global Initiative for Chronic Obstructive Lung Disease (GOLD) groups B, C, and D. MAIN BODY: Tiotropium bromide was the first LAMA available for COPD in clinical practice and, because of its long duration of action, is administered once daily. Tiotropium was initially available as an inhalation powder delivered via a dry-powder inhaler (DPI). Later, tiotropium also became available as an inhalation spray delivered via a soft mist inhaler (SMI). The SMI was designed to overcome or minimize some of the issues associated with other inhaler types (eg, the need for strong inspiratory airflow with DPIs). Results of short- and long-term randomized, controlled clinical trials of tiotropium in patients with COPD indicated tiotropium was safe and significantly improved lung function, health-related quality of life, and exercise endurance, and reduced dyspnea, lung hyperinflation, exacerbations, and use of rescue medication compared with placebo or active comparators. These positive efficacy findings triggered the evaluation of tiotropium in fixed-dose combination with olodaterol (a long-acting ß2-agonist). In this review, we provide an overview of studies of tiotropium for the treatment of COPD, with a focus on pivotal studies. CONCLUSION: Tiotropium is safe and efficacious as a long-term, once-daily LAMA for the maintenance treatment of COPD and for reducing COPD exacerbations. The SMI generates a low-velocity, long-duration aerosol spray with a high fine-particle fraction, which results in marked lung drug deposition. In addition, high inspiratory flow rates are not required.

Device use errors with soft mist inhalers: A global systematic literature review and meta-analysis.

Inhaled bronchodilators are the cornerstone of treatment for chronic obstructive pulmonary disease (COPD). Soft mist inhalers (SMIs) are devices that deliver bronchodilators. Although correct device use is paramount to successful medication delivery, patient errors are common. This global systematic literature review and meta-analysis examined device use errors with SMIs among patients with obstructive lung diseases. PubMed, EMBASE, PsycINFO, Cochrane, and Google Scholar were searched to identify studies published between 2010 and 2019 that met the following inclusion criteria: (a) English language; (b) a diagnosis of COPD, bronchitis, or emphysema; and (c) reported device use errors among adults receiving long-acting bronchodilator treatment with Respimat® SMI (i.e. Spiriva®, Stiolto®, Spiolto®, and Striverdi®). Descriptive statistics examined sociodemographics, clinical characteristics, and device use errors. Meta-analysis techniques were employed with random-effects models to generate pooled mean effect sizes and 95% confidence intervals (CIs) for overall and step-by-step errors. The I2 statistic measured heterogeneity. Twelve studies (n = 1288 patients) were included in this meta-analysis. Eighty-eight percent of patients had COPD, and most had moderate/very severe airflow limitation (Global Initiative for Chronic Obstructive Lung Disease spirometric stages II to IV). Aggregate results revealed that 58.9% (95% CI: 42.4-75.5; I2 = 92.8%) of patients made ≥1 device use errors. Among 11 studies with step-by-step data, the most common errors were failure to (1) exhale completely and away from the device (47.8% (95% CI: 33.6-62.0)); (2) hold breath for up to 10 seconds (30.6% (95% CI: 17.5-43.7)); (3) take a slow, deep breath while pressing the dose release button (27.9% (95% CI: 14.5-41.2)); (4) hold the inhaler upright (22.6% (95% CI: 6.2-39.0)); and (5) turn the base toward the arrows until it clicked (17.6% (95% CI: 3.0-32.2)). Device use errors occurred in about 6 of 10 patients who used SMIs. An individualized approach to inhalation device selection and ongoing training and monitoring of device use are important in optimizing bronchodilator treatment.

Evaluation of patients' real-world post-dispensing use and storage environments of tiotropium bromide Respimat® soft mist inhaler on its in vitro dose delivery and lung deposition.

BACKGROUND: Oral inhalation is the main drug delivery route for treating obstructive lung conditions. Thus, many inhaler devices with various design and pharmaceutical formulation have been introduced. The fine particle dose (FPD) and mass median aerodynamic diameter (MMAD ≤ 5 µm) of the aerosol delivered dose (DD) dictate the therapeutically effective peripheral lung deposition. This study evaluated the in vitro aerosol emission performance of tiotropium bromide emitted from Spiriva® Respimat® soft mist inhalers (R) after living under patients' real-world, post-dispensing handling environments. METHODS: This was a two-stage investigation. In the first clinical stage, research ethical approval was obtained to enrol patients already been using R for at least 3 months. Those who signed consent were given both new R to use and temperature and relative humidity (RH) handheld, portable data loggers to keep in the vicinity of the given R. The participants returned the given R and data loggers after 2 weeks. Patient recruitment took place in Amman, Jordan, during the summer (RS) and winter (RW). Subsequently, in the second laboratory stage, other R were strictly stored at an average of 21.0 °C and 46.9% RH as control (RC). The Next Generation Impactor (NGI) was used to evaluate the RS, RW and RC. The NGI was operated at a flow rate of 30 L/min. RESULTS: The RS were exposed to an average (range) 23.6 °C (18.2-37.5 °C) and 43.8% RH (21.4-60.0% RH) that were statistically comparable (p > 0.05) to that of the RW; 17.3 °C (13.2-26.7 °C) and 52.8% RH (26.3-69.1% RH). The RW and RC retention environments were statistically different (p < 0.05), whilst the RS and RC had comparable (p > 0.05) conditions. No significant differences (p > 0.05) were found in the tiotropium bromide DD (2.39 vs 2.43 µg), FPD (0.88 vs 0.90 µg) and MMAD (5.1 vs 4.98 µm) between the RS and RW, respectively. Compared to the RC inhalers, both the RS and RW devices had significantly higher FPD and relatively smaller tiotropium bromide particles. CONCLUSIONS: Using the R under the fluctuating summer and winter environments of our patients would not affect its overall tiotropium bromide emission performance. The significant increase in the respirable mass of the RS and RW might be offset by the increase in particles <1 µm particularly in patients with poor inhaler technique.

Risk Factors Associated with Misuse of Soft Mist Inhaler in Patients with Chronic Obstructive Pulmonary Disease.

Purpose: The use of inhaled bronchodilators is the mainstay of treatment for patients with chronic obstructive pulmonary disease (COPD). Although the soft mist inhaler (SMI) was developed to overcome the disadvantages of pressurized metered dose and drug powder inhalers, misuse during handling has been frequently observed in many studies. However, few studies have focused on SMI misuse among patients with COPD. Thus, we aimed to assess and identify the risk factors associated with SMI misuse among patients with COPD. Patient and Methods: In this prospective, observational, cross-sectional study, we enrolled patients with COPD who were undergoing SMI treatment between January 2018 and March 2020. An advanced nurse practitioner assessed the participants' handling of the device by using a check list. Results: Among 159 participants, 136 (85.5%) reported inhaler misuse. Duration of COPD and COPD assessment test (CAT) scores were positively associated with inhaler misuse; adherence and education level were negatively associated with inhaler misuse. In the multivariable analysis, a low educational level (less than high school), high CAT score (≥ 10), and short duration of COPD (≤ 2 years) were identified as risk factors for SMI misuse. Conclusion: SMI misuse remains common among patients with COPD. Therefore, clinicians should pay close attention to their patients using SMIs, especially in the early period after the diagnosis of COPD.

Aerosol Plumes of Inhalers Used in COPD.

INTRODUCTION: The selection of inhaler device is of critical importance in chronic obstructive pulmonary disease (COPD) as the interaction between a patient's inhalation profile and the aerosol characteristics of an inhaler can affect drug delivery and lung deposition. This study assessed the in vitro aerosol characteristics of inhaler devices approved for the treatment of COPD, including a soft mist inhaler (SMI), pressurized metered-dose inhalers (pMDIs), and dry powder inhalers (DPIs). METHODS: High-speed video recording was used to visualize and measure aerosol velocity and spray duration for nine different inhalers (one SMI, three pMDIs, and five DPIs), each containing dual or triple fixed-dose combinations of long-acting muscarinic receptor antagonists and long-acting ß2-agonists, with or without an inhaled corticosteroid. Measurements were taken in triplicate at experimental flow rates of 30, 60, and 90 l/min. Optimal flow rates were defined based on pharmacopoeial testing requirements: 30 l/min for pMDIs and SMIs, and the rate achieving a 4-kPa pressure drop against internal inhaler resistance for DPIs. Comparison of aerosol plumes was based on the experimental flow rates closest to the optimal flow rates. RESULTS: The Respimat SMI had the slowest plume velocity (0.99 m/s) and longest spray duration (1447 ms) compared with pMDIs (velocity: 3.65-5.09 m/s; duration: 227-270 ms) and DPIs (velocity: 1.43-4.60 m/s; duration: 60-757 ms). With increasing flow rates, SMI aerosol duration was unaffected, but velocity increased (maximum 2.63 m/s), pMDI aerosol velocity and duration were unaffected, and DPI aerosol velocity tended to increase, with a more variable impact on duration. CONCLUSIONS: Aerosol characteristics (velocity and duration of aerosol plume) vary by inhaler type. Plume velocity was lower and spray duration longer for the SMI compared with pMDIs and DPIs. Increasing experimental flow rate was associated with faster plume velocity for DPIs and the SMI, with no or variable impact on plume duration, whereas pMDI aerosol velocity and duration were unaffected by increasing flow rate.

Use of tiotropium Respimat Soft Mist Inhaler versus HandiHaler and mortality in patients with COPD.

Tiotropium, a long-acting anticholinergic, is delivered via HandiHaler or via Respimat. Randomised controlled trials suggest that use of tiotropium Respimat increases the risk of dying. We compared the risk of mortality between tiotropium Respimat versus HandiHaler. Within the Integrated Primary Care Information database, we defined a source population of patients, aged ≥ 40 years, with ≥ 1 year of follow-up. Based on prescription data, we defined episodes of tiotropium use (Respimat or HandiHaler). The risk of mortality, within these episodes, was calculated using a Cox proportional hazard regression analysis. From the source population, 11 287 patients provided 24 522 episodes of tiotropium use. 496 patients died while being exposed to HandiHaler or Respimat. Use of Respimat was associated with almost 30% increased risk of dying (adjusted HR 1.27, 95% CI 1.03-1.57) with the highest risk for cardiovascular/cerebrovascular death (adjusted HR 1.56, 95% CI 1.08-2.25). The risk was higher in patients with co-existing cardiovascular disease (adjusted HR 1.36, 95% CI 1.07-1.73) than in patients without (adjusted HR 1.02, 95% CI 0.61-1.71). Use of tiotropium Respimat was associated with an almost 30% increase of mortality compared with HandiHaler and the association was the strongest for cardiovascular/cerebrovascular death. It is unclear whether this association is causal or due to residual confounding by chronic obstructive pulmonary disease severity.

Delivery technology of inhaled therapy for asthma and COPD.

Inhaled therapy is the cornerstone of the management of asthma and chronic obstructive pulmonary disease (COPD). Drugs such as bronchodilators and corticosteroids are administered directly to the airways for local effect and rapid onset of action while systemic exposure and side effects are minimized. There are four major types of inhaler devices used clinically to generate aerosols for inhalation, namely, pressurized metered-dose inhalers (pMDIs), nebulizers, Soft Mist™ inhalers (SMIs) and dry powder inhalers (DPIs). Each of them has its own unique characteristics that can target different patient groups. For instance, patients' inhaler technique is critical for pMDIs and SMIs to achieve proper drug deposition in the lung, which could be challenging for some patients. Nebulizers are designed to deliver aerosols to patients during tidal breathing, but they require electricity to operate and are less portable than other devices. DPIs are the only device that delivers aerosols in dry powder form with better stability, but they rely on patients' inspiration effort for powder dispersion, rendering them unsuitable for patients with compromised lung function. Choosing a device that can cater for the need of individual patient is paramount for effective inhaled therapy. This chapter provides an overview of inhaled therapy for the management of asthma and COPD. The operation principles, merits and limitations of different delivery technologies are examined. Looking ahead, the challenges of delivering novel therapeutics such as biologics through the pulmonary route are also discussed.

Optimization of formulation and atomization of lipid nanoparticles for the inhalation of mRNA.

Lipid nanoparticles (LNPs) have demonstrated efficacy and safety for mRNA vaccine administration by intramuscular injection; however, the pulmonary delivery of mRNA encapsulated LNPs remains challenging. The atomization process of LNPs will cause shear stress due to dispersed air, air jets, ultrasonication, vibrating mesh etc., leading to the agglomeration or leakage of LNPs, which can be detrimental to transcellular transport and endosomal escape. In this study, the LNP formulation, atomization methods and buffer system were optimized to maintain the LNP stability and mRNA efficiency during the atomization process. Firstly, a suitable LNP formulation for atomization was optimized based on the in vitro results, and the optimized LNP formulation was AX4, DSPC, cholesterol and DMG-PEG2K at a 35/16/46.5/2.5 (%) molar ratio. Subsequently, different atomization methods were compared to find the most suitable method to deliver mRNA-LNP solution. Soft mist inhaler (SMI) was found to be the best for pulmonary delivery of mRNA encapsulated LNPs. The physico-chemical properties such as size and entrapment efficiency (EE) of the LNPs were further improved by adjusting the buffer system with trehalose. Lastly, the in vivo fluorescence imaging of mice demonstrated that SMI with proper LNPs design and buffer system hold promise for inhaled mRNA-LNP therapies.

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.

Visualization and Estimation of Nasal Spray Delivery to Olfactory Mucosa in an Image-Based Transparent Nasal Model.

Background: Nose-to-brain (N2B) drug delivery offers unique advantages over intravenous methods; however, the delivery efficiency to the olfactory region using conventional nasal devices and protocols is low. This study proposes a new strategy to effectively deliver high doses to the olfactory region while minimizing dose variability and drug losses in other regions of the nasal cavity. Materials and Methods: The effects of delivery variables on the dosimetry of nasal sprays were systematically evaluated in a 3D-printed anatomical model that was generated from a magnetic resonance image of the nasal airway. The nasal model comprised four parts for regional dose quantification. A transparent nasal cast and fluorescent imaging were used for visualization, enabling detailed examination of the transient liquid film translocation, real-time feedback on input effect, and prompt adjustment to delivery variables, which included the head position, nozzle angle, applied dose, inhalation flow, and solution viscosity. Results: The results showed that the conventional vertex-to-floor head position was not optimal for olfactory delivery. Instead, a head position tilting 45-60° backward from the supine position gave a higher olfactory deposition and lower variability. A two-dose application (250 mg) was necessary to mobilize the liquid film that often accumulated in the front nose following the first dose administration. The presence of an inhalation flow reduced the olfactory deposition and redistributed the sprays to the middle meatus. The recommended olfactory delivery variables include a head position ranging 45-60°, a nozzle angle ranging 5-10°, two doses, and no inhalation flow. With these variables, an olfactory deposition fraction of 22.7 ± 3.7% was achieved in this study, with insignificant discrepancies in olfactory delivery between the right and left nasal passages. Conclusions: It is feasible to deliver clinically significant doses of nasal sprays to the olfactory region by leveraging an optimized combination of delivery variables.

FIDEPOC: Consensus on Inspiratory Flow and Lung Deposition as Key Decision Factors in COPD Inhaled Therapy.

Purpose: The pharmacological treatment of chronic obstructive pulmonary disease (COPD) is largely based on inhaled bronchodilators. Inspiratory flow and lung deposition are key parameters to be considered in inhaled therapy; however, the relationship between these two parameters, the patient specificities, and the suitability of the inhaler type for COPD management has not been fully addressed. The present study follows a Delphi Panel methodology to find expert consensus on the role of inspiratory flow and lung deposition as key decision factors in COPD inhaled therapy. Methods: A two-round Delphi Panel, consisting of 38 statements (items) and completed by 57 Spanish pulmonologists, was carried out to measure the experts' consensus degree with each item. Results: A high degree of consensus was reached on most of the items consulted, among these inspiratory flow or inspiratory capacity should be periodically considered when choosing an inhalation device and to ensure the suitability of the inhaler used; the outflow velocity and particle size of the different devices should be considered to ensure adequate lung deposition; an active device (pressurized metered-dose inhalers (pMDI) or soft mist inhalers (SMI)) should be used in patients with low inspiratory flow to achieve adequate lung deposition; and, the use of dry powder inhalers (DPI) should be re-evaluated in patients with severe obstruction and severe exacerbations. Conclusion: This study shows the relevance of inspiratory flow and the degree of particle deposition in the lung in the choice of an inhalation device for COPD management, as well as the convenience of an SMI type device in cases of low inspiratory flow. Moreover, it highlights the scarcity of information on the specific features of inhalation devices in COPD guidelines.

Early Effects of Low Molecular Weight Heparin Therapy with Soft-Mist Inhaler for COVID-19-Induced Hypoxemia: A Phase IIb Trial.

In COVID-19-induced acute respiratory distress syndrome, the lungs are incapable of filling with sufficient air, leading to hypoxemia that results in high mortality among hospitalized patients. In clinical trials, low-molecular-weight heparin was administered via a specially designed soft-mist inhaler device in an investigator initiated, single-center, open-label, phase-IIb clinical trial. Patients with evidently worse clinical presentations were classed as the "Device Group"; 40 patients were given low-molecular-weight heparin via a soft mist inhaler at a dose of 4000 IU per administration, twice a day. The Control Group, also made up of 40 patients, received the standard therapy. The predetermined severity of hypoxemia and the peripheral oxygen saturation of patients were measured on the 1st and 10th days of treatment. The improvement was particularly striking in cases of severe hypoxemia. In the 10-day treatment, low-molecular-weight heparin was shown to significantly improve breathing capability when delivered via a soft-mist inhaler.

In Vitro Measurements of Spiriva Respimat Dose Delivery in Mechanically Ventilated Tracheostomy Patients.

Background: For patients with severe chronic obstructive pulmonary disease under invasive mechanical ventilation, medication for aerosol therapy is delivered through tracheostomy or endotracheal airways. Typically, these medications (such as bronchodilators) are long-acting formulations that are delivered through Soft Mist™ Inhalers (SMI), or Pressurized Metered-Dose Inhalers. The Respimat® SMI has been shown to have increased efficiency because of its slow and prolonged aerosol mist and has gained popularity in clinical settings. However, the Respimat was not designed for drug delivery through artificial airways. Therefore, there is a need for SMI adapters in intensive care for use in mechanical ventilator circuits. The purpose of this study was to evaluate the performance of a new Respimat adapter (ODAPT™ for mechanical ventilator [ODAPT MV]) for use in mechanical ventilator circuits which, in combination with a Pulmodyne T-piece adapter, allows use without interruption of the circuit in case of medication replacement. Methods: Tiotropium delivery to the lungs, using Respimat, was assessed using the ODAPT MV adapter within an in vitro setup, including a three-dimensional printed trachea model and a mechanical ventilator. Medication deposition and losses were investigated using two commonly used tracheostomy tube (TT) sizes (6 and 8 mm inner canula) for two flow rates (45 and 60 L/min) under different conditions (30%-50%. and 100% relative humidity [RH]). Medication delivery using the ODAPT MV adapter was compared with the RTC-26C in-line adapter under similar conditions (8 mm TT size, 100% RH at 45 L/min). Results: It was found that 7.1%-13.4% of the nominal dose (ND) was lost in the ODAPT MV adapter for different TT size, RH, and flow rates used. Higher losses were found in the inhaler's mouthpiece ranging from 15.7% to 29.1% ND. The percentage of the delivered medication reaching the lungs was determined to be 13.7%-18.5% ND delivered without significant differences between the experimental conditions tested. The ODAPT MV performed well compared with the RTC-26C under similar conditions (17.9% and 16.6% ND, respectively). Conclusion: The medication delivered through mechanical ventilation using the ODAPT MV adapter represents about one third the dose delivered directly through the Respimat SMI in vivo.

Optimal Connection for Tiotropium SMI Delivery through Mechanical Ventilation: An In Vitro Study.

We aimed to quantify Soft Mist Inhalers (SMI) delivery to spontaneous breathing model and compare with different adapters via endotracheal tube during mechanical ventilation or by manual resuscitation. A tiotropium SMI was used with a commercial in-line adapter and a T-adapter placed between the Y-adapter and the inspiratory limb of the ventilator circuit during mechanical ventilation. The SMI was actuated at the beginning of inspiration and expiration. In separate experiments, a manual resuscitator with T-adapter was attached to endotracheal tube, collecting filter, and a passive test lung. Drug was eluted from collecting filters with salt-based solvent and analyzed using high-performance liquid chromatography. Results showed the percent of SMI label dose inhaled was 3-fold higher with the commercial in-line adapter with actuation during expiration than when synchronized with inspiration. SMI with T-adapter delivery via ventilator was similar to inhalation (1.20%) or exhalation (1.02%), and both had lower delivery dose than with manual resuscitator (2.80%; p = 0.01). The inhaled dose via endotracheal tube was much lower than inhaled dose with spontaneous breathing (22.08%). In conclusion, the inhaled dose with the commercial adapter was higher with SMI actuated during expiration, but still far less than reported spontaneous inhaled dose.

Technical Evaluation of Soft Mist Inhaler Use in Patients with Chronic Obstructive Pulmonary Disease: A Cross-Sectional Study.

Background: Proper inhaler technique is highly relevant to the effective management of chronic obstructive pulmonary disease (COPD). The tiotropium bromide spray (TBS) (Spiriva® Respimat®) is a soft mist inhaler (SMI) preferred by patients to pressurized metered-dose inhalers (pMDIs) and dry powder inhalers (DPIs) because of its convenience in use. However, the technique of using TBS inhaler in the real world is unclear. Objective: To evaluate techniques in using TBS inhaler and investigate the association between the patient characteristics and the correct use of TBS inhaler. Methods: This cross-sectional study enrolled 74 COPD patients who used TBS inhaler device for more than 3 months. The sociodemographic and clinical characteristics of the patients were recorded. The technique of using TBS inhaler was evaluated step by step. Incorrect use was defined as the patient's inability to complete the key steps in the inhalation manoeuvre. The percentage of incorrect use was compared between the groups. Risk factors related to incorrect use were analyzed by logistic regression analysis. Results: Of the 74 participants, only 2 (2.7%) patients completed all the steps correctly, and 48 (64.9%) patients misused the key steps in the inhalation manoeuvre. Incorrect preparation of the TBS inhaler for the first use was the most frequently misused step, accounting for 77.0%. Factors associated with misuse of TBS inhaler included the educational background (p=0.010), living state (p=0.031) and COPD assessment test (CAT) score (p=0.005) of the patients. Additionally, logistic regression analysis showed that the COPD duration was significantly associated with the incorrect use (p=0.019). Compared with patients with a higher educational background, patients with an elementary school background [OR 11652.99, CI: 22.72-5975697.72], junior high school background [OR 7187.78, CI: 16.41-3146787] and high school background [OR 1563, CI: 4.27-572329.67] were more likely to misuse TBS inhaler. Patients living with their spouses alone were also more likely to commit errors in using TBS inhaler as compared with those living with their children [OR 12.29, CI of 1.14-1.96]. Clinical factors like the COPD symptoms were relative to the technical use of the device. Better technique was accompanied by a lower CAT score [OR 1.49, CI of 1.14-1.96]. Conclusion: The incorrect use of TBS inhaler was common in COPD patients. Healthcare providers should not only teach the patients about the drug preparation but help them use the inhaler correctly. Special attention should be paid to patients with a short COPD duration and a low educational background and those who live without the company of their children. Proper use of TBS inhaler can significantly improve the symptom control of COPD patients.

Advances in pulmonary drug delivery devices for the treatment of chronic obstructive pulmonary disease.

Introduction: Proper device selection is crucial for the clinical results of inhalation therapy. However, none of the available devices fully conforms to the requirements for delivering drug with increased patient adherence, and we are still looking for the ideal inhaler. For this reason, there are several ongoing technical innovations to improve inhaler devices.Areas covered: Progress in pulmonary drug delivery device technology is examined, focusing on innovations in pressurized metered dose inhalers, dry powder inhalers, nebulizers, and soft mist inhalers.Expert opinion: Both formulation improvements and new device technologies have been developed over the last couple of decades through an improved understanding of the mechanisms of aerosolization and lung deposition. Digital health is offering the potential to produce inhalers with a wider range of monitoring capabilities, but further studies are needed, in particular as regards the analysis of cost-effectiveness. Furthermore, there are still substantial issues that must be overcome in order to continually innovate and improve targeted inhaled drug delivery to the lungs. In any case, there are other potential therapeutic possibilities for COPD in development that may be administered by inhalation, whose clinical use requires advances and improvements in the devices used for administration.

In Vitro Evaluation of Aerosol Performance and Delivery Efficiency During Mechanical Ventilation Between Soft Mist Inhaler and Pressurized Metered-Dose Inhaler.

BACKGROUND: Soft mist inhalers (SMIs) generate aerosols with a smaller particle size than pressurized metered-dose inhalers (pMDIs). However, the whole-span particle size distribution (PSD) of SMIs and the optimal delivery method of SMIs during mechanical ventilation have not been fully investigated. This study aimed to measure the PSD of the SMI alone and the SMI coupled to an inhalation aid (eg, a spacer, a valved holding chamber), as well as the delivery efficiency of SMI in different actuation timings and circuit positions during mechanical ventilation. As a suitable comparison, the pMDI was chosen for the same measurement. METHODS: SMIs (2.5 µg/actuation of tiotropium) were compared with pMDIs (100 µg/actuation of salbutamol). A microorifice uniform deposit impactor was utilized for the particle sizing of drug aerosols generated by inhalers alone, inhalers with a spacer, and inhalers with a valved holding chamber. To optimize the delivery efficiency of both inhalers during mechanical ventilation, the operating parameters included the circuit positions and actuation timings in the ventilator circuit. Particle sizes and inhaled doses were measured with an optical particle sizer and filters used to collect and quantify the drug, respectively. RESULTS: The SMI generated a smaller mass medium aerodynamic diameter (MMAD) than that from the pMDI. The extrafine-particle fraction (EFPF, < 1 µm) of the SMI was significantly higher than that of the pMDI. With the use of either inhalation aid, the MMAD of both inhalers decreased, and both inhalers with inhalation aid showed significant increases in EFPF. During mechanical ventilation, the optimum way to deliver the SMI and pMDI was at 15 cm from the Y-piece and actuated at the end of expiration and the onset of inspiration, respectively. CONCLUSIONS: The SMI with an inhalation aid showed marginal improvement on the PSD. The inhaler type, actuation timing, and position within the circuit also played important roles in delivery efficiency during mechanical ventilation.

Healthcare Resource Utilization, Exacerbations, and Readmissions Among Medicare Patients with Chronic Obstructive Pulmonary Disease After Long-Acting Muscarinic Antagonist Therapy Initiation with Soft Mist versus Dry Powder Inhalers.

Background: Chronic obstructive pulmonary disease (COPD) is often managed with inhaled long-acting muscarinic antagonists (LAMAs), yet real-world data on healthcare resource utilization (HRU) by inhaler type are lacking. This study compared HRU after LAMA initiation with a soft mist inhaler (SMI) versus a dry powder inhaler (DPI). Patients and Methods: Inclusion criteria were COPD diagnosis, age ≥40 years, LAMA initiation (index date = first LAMA SMI or DPI claim 9/1/14-6/30/18), and Medicare Advantage enrollment 1 year pre-index (baseline) to ≥30 days post-index (follow-up). Patients were followed to the earliest of discontinuation, switch, disenrollment, 1 year, or study end (7/31/18). Exclusion criteria were asthma, cystic fibrosis, or lung cancer diagnoses, unavailable demographics, multiple index LAMAs, or baseline LAMA use. Cohorts (SMI or DPI) were balanced on baseline characteristics using inverse probability of treatment weighting. Outcomes included per patient per month (PPPM) COPD-related HRU encounters, and exacerbations (defined as moderate [ambulatory visit with corticosteroid or antibiotic within ±7 days] or severe [emergency visit or inpatient admission]); and 30-day readmissions following COPD-related hospitalizations. Results: After weighting, cohorts (SMI [n=5360] and DPI [n=22,880]) were similar in age (72 and 73 years, respectively), gender (both 52% female), and COPD severity score (31.3 and 31.5, respectively). Cohorts had similar counts of follow-up HRU encounters. However, the SMI cohort had fewer (mean ± standard deviation) COPD-related exacerbations (0.054±0.082 vs DPI cohort 0.059±0.088 PPPM, p<0.001) overall. Moreover, the SMI cohort had fewer severe exacerbations (0.030±0.058 vs DPI: 0.034±0.065 PPPM, p<0.001). Hospitalizations among SMI patients had a lower adjusted odds of readmission versus hospitalizations among DPI patients (odds ratio: 0.656, 95% confidence interval= 0.460, 0.937; p=0.020). Conclusion: SMI initiators had significantly fewer COPD-related exacerbations than DPI initiators. In addition, lower odds of readmissions were observed following COPD-related hospitalizations among the SMI cohort, as compared with the DPI cohort.

Reduced Environmental Impact of the Reusable Respimat® Soft Mist™ Inhaler Compared with Pressurised Metered-Dose Inhalers.

INTRODUCTION: Pressurised metered-dose inhalers (pMDIs) are associated with global warming potential values as they contain a hydrofluoroalkane (HFA) propellant, whereas the Respimat® Soft Mist™ inhaler is propellant-free. The original disposable Respimat has recently been updated to provide a reusable device that is similar in performance and use but is more convenient to patients and reduces environmental impact. This study compared the product carbon footprint (PCF) of Respimat (both disposable and reusable) and pMDIs to understand life cycle hotspots, and also to determine the potential quantitative environmental benefits of a reusable Respimat product. METHODS: PCFs of four inhalation products-tiotropium bromide (Spiriva®) Respimat, ipratropium bromide/fenoterol hydrobromide (Berodual®) Respimat, Berodual HFA pMDI and ipratropium bromide (Atrovent®) HFA pMDI-were assessed across their whole life cycle. RESULTS: Data show that Respimat inhalers have a lower PCF (carbon dioxide equivalent per kilogram) than HFA pMDIs: pMDI Atrovent 14.59; pMDI Berodual 16.48; disposable Spiriva Respimat 0.78; disposable Berodual Respimat 0.78. Approximately 98% of the pMDI life cycle total is due to HFA propellant emissions during use and end-of-life phases. The impact of the material used for the Respimat product outweighs the impact of the material used to make the empty cartridge. Furthermore, compared with the single-use device over 1 month, the PCF of Spiriva Respimat was further reduced by 57% and 71% using the device with refill cartridges over 3 and 6 months, respectively. CONCLUSION: Together, these data suggest that Respimat inhalers, and in particular the new reusable inhaler, can reduce the environmental impact associated with inhaler use. FUNDING: Boehringer Ingelheim.