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Concept: Inhaler


Background Studies have suggested an association between frequent acetaminophen use and asthma-related complications among children, leading some physicians to recommend that acetaminophen be avoided in children with asthma; however, appropriately designed trials evaluating this association in children are lacking. Methods In a multicenter, prospective, randomized, double-blind, parallel-group trial, we enrolled 300 children (age range, 12 to 59 months) with mild persistent asthma and assigned them to receive either acetaminophen or ibuprofen when needed for the alleviation of fever or pain over the course of 48 weeks. The primary outcome was the number of asthma exacerbations that led to treatment with systemic glucocorticoids. Children in both groups received standardized asthma-controller therapies that were used in a simultaneous, factorially linked trial. Results Participants received a median of 5.5 doses (interquartile range, 1.0 to 15.0) of trial medication; there was no significant between-group difference in the median number of doses received (P=0.47). The number of asthma exacerbations did not differ significantly between the two groups, with a mean of 0.81 per participant with acetaminophen and 0.87 per participant with ibuprofen over 46 weeks of follow-up (relative rate of asthma exacerbations in the acetaminophen group vs. the ibuprofen group, 0.94; 95% confidence interval, 0.69 to 1.28; P=0.67). In the acetaminophen group, 49% of participants had at least one asthma exacerbation and 21% had at least two, as compared with 47% and 24%, respectively, in the ibuprofen group. Similarly, no significant differences were detected between acetaminophen and ibuprofen with respect to the percentage of asthma-control days (85.8% and 86.8%, respectively; P=0.50), use of an albuterol rescue inhaler (2.8 and 3.0 inhalations per week, respectively; P=0.69), unscheduled health care utilization for asthma (0.75 and 0.76 episodes per participant, respectively; P=0.94), or adverse events. Conclusions Among young children with mild persistent asthma, as-needed use of acetaminophen was not shown to be associated with a higher incidence of asthma exacerbations or worse asthma control than was as-needed use of ibuprofen. (Funded by the National Institutes of Health; AVICA number, NCT01606319 .).

Concepts: Asthma, Median, Interquartile range, Paracetamol, Aspirin, Normal distribution, Inhaler, Nebulizer


Problems with the use of inhalers by patients were noted shortly after the launch of the metered dose inhaler (MDI) and persist today. We aimed to assess the most common errors in inhaler use over the last 40 years in patients treated with MDI or dry powder inhalers (DPI).

Concepts: Asthma, Patient, Metered-dose inhaler, Dry powder inhaler, Dosage forms, Inhaler, Nebulizer, Drug delivery devices


An interaction between device resistance and inhalation flow provides the ‘energy’ to de-aggregate the metered dose of a dry powder inhaler (DPIs). Hence all dry powder inhalers demonstrate flow dependent dose emission but information on this at low flows is not available. We have adapted the compendial method for the Andersen Cascade Impactor (ACI) to include a mixing inlet to determine the aerodynamic dose emission characteristics of a salbutamol Diskus® [DSK], Easyhaler® [EASY] and Clickhaler® [CLICK] and the terbutaline Turbuhaler® [TBH] using flows of 10-60L/min and inhalation volumes of 2 and 4L. All DPIs demonstrated flow dependent dose emission (p<0.001) but there was no difference in the measurements between 2 and 4L. The flow dependent dose emission properties of each DPI started to plateau when the pressure change inside each device, during an inhalation, was between 1-1.5kPa. This corresponds to inhalation flows of 40.1-49.1, 25.4-28.9, 23.6-28.9 and 29.7-36.3L/min through DSK, CLICK, TBH, and EASY. The adapted methodology allows measurements at low flows. The results highlight that the compendial methodology to use an inhaled volume of 4L with the ACI could be replaced by 2L and that the recommendation to make measurements using a pressure drop of 4kPa should be revised.

Concepts: Asthma, Volume, Thermodynamics, Metered-dose inhaler, Dry powder inhaler, Dosage forms, Inhaler, Nebulizer


Inhalers are devices employed to deliver medication to the airways in the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease. A dry powder inhaler (DPI) is a breath actuated inhaler that delivers medication in dry powder form. When used correctly, DPIs improve patients' clinical outcomes. However, some patients are unable to reach the peak inspiratory flow rate (PIFR) necessary to fully extract the medication. Presently clinicians have no reliable method of objectively measuring PIFR in inhalers. In this study, we propose a novel method of estimating PIFR and also the inspiratory capacity (IC) of patients' inhalations from a commonly used DPI, using acoustic measurements. With a recording device, the acoustic signal of 15 healthy subjects using a DPI over a range of varying PIFR and IC values was obtained. Temporal and spectral signal analysis revealed that the inhalation signal contains sufficient information that can be employed to estimate PIFR and IC. It was found that the average power (Pave) in the frequency band 300-600 Hz had the strongest correlation with PIFR (R(2) = 0.9079), while the power in the same frequency band was also highly correlated with IC (R(2) = 0.9245). This study has several clinical implications as it demonstrates the feasibility of using acoustics to objectively monitor inhaler use.

Concepts: Medicine, Asthma, Chronic obstructive pulmonary disease, Respiratory system, Metered-dose inhaler, Dry powder inhaler, Dosage forms, Inhaler


Objectives: The objective of this randomised, cross-over study was to compare a new single-dose dry powder inhaler (Elpenhaler (EH)), with a widely used, multi-dose dry powder inhaler (Diskus (DK)) on critical errors, patient preference, and satisfaction with the inhalers. Methods: First, patients read the instructions of one device, followed by a first inhalation attempt. Inhalation errors were assessed and if mistakes were made, correct inhaler use was demonstrated. Then patients had to demonstrate again and mistakes were registered. This was repeated up to four times. After completing the first device, the same procedure was started with the second inhaler. Primary outcome was the percentage of patients making at least one critical error after reading the insert. Secondary outcomes were inhaler preference and satisfaction with the inhalers. Results: After reading the insert, 19 of 113 patients (17%) made at least one critical error with DK and 40 (35%) with EH (p = 0.001); 73% preferred the DK and 27% the EH (p < 0.001). The mean overall satisfaction score (1 = very satisfied; 5 = very dissatisfied) for DK was 1.59 and for EH 2.48 (p < 0.001). Conclusion: With DK fewer errors were made, more patients preferred DK over EH and patients were more satisfied with DK. This may enable DK to improve treatment outcomes more than EH.

Concepts: Asthma, Chronic obstructive pulmonary disease, Error, Metered-dose inhaler, Dry powder inhaler, Dosage forms, Inhaler, Drug delivery devices


Objective: To assess preference, satisfaction and critical errors with a novel, breath-actuated, multi-dose dry powder inhaler (DPI; Genuair®/Pressair™), versus a widely used, single-dose DPI (HandiHaler®) in patients with moderate-to-severe chronic obstructive pulmonary disease. Methods: In this randomised, open-label, multicentre, cross-over study, patients (aged ≥ 40 years) inhaled placebo once daily through both inhalers for 2 weeks in addition to current medication. The primary end point was percentage of patients who preferred Genuair to HandiHaler. Overall patient satisfaction (5-point scale: 1 = very dissatisfied; 5 = very satisfied), critical errors and willingness to continue using each inhaler (0 = not willing; 100 = definitely willing) were assessed. Results: Of 130 patients randomised, 105 were included in the intent-to-treat population (71.4% male; mean age 65.7 years). After 2 weeks, significantly more patients preferred Genuair than HandiHaler (79.1 vs 20.9%; p < 0.0001). Overall satisfaction scores (4.6 vs 3.8; p < 0.0001) and willingness to continue use scores (84.0 vs 62.5; p < 0.0001) were significantly higher with Genuair versus HandiHaler. Significantly fewer patients made ≥ 1 critical error with Genuair only compared with HandiHaler only (2.9 vs 19.0%; p < 0.0001). Conclusion: After 2 weeks' practice, patients preferred and were more willing to continue using Genuair than HandiHaler. Genuair was associated with higher patient satisfaction and fewer critical errors than HandiHaler.

Concepts: Asthma, Medical terms, Chronic obstructive pulmonary disease, Metered-dose inhaler, Dry powder inhaler, Dosage forms, Inhaler, Drug delivery devices


Asthma is an increasing pathology with poor compliance. Achievement of control is possible but under intensive treatment. In this setting, fluticasone/salmeterol association delivered by dry powder inhalers is a valuable and proved option. A prospective, parallel, open-label, phase IV, multicentre non-inferiority study was conducted to determine therapeutic similarity between 2 different inhalers: Generic DPI and Diskus®, which both deliver a fluticasone/salmeterol association (CAS 80474-14-2/CAS 89365-50-4). A 103 uncontrolled asthmatic patients were randomly assigned in 2 groups, Generic (G) and Diskus® (D), and received the association for 18 weeks through the appropriate device. They were evaluated according to Asthma Quality of Life Questionnaire and GINA/NIH guidelines. To demonstrate non-inferiority, the estimation of the Relative Risk between the Global Score Rate per group with its 95% confidence interval was calculated and compared against a non-inferiority margin obtained from a previous study. The Global Score Rate was 82% for G Group and 83% for D Group. The RR was 1.0124 (95% CI: 0.847-1.210). The margin set at 0.832 was not reached by the lower 95% CI (z=-2.097; p=0.018) pointing out non-inferiority. The results have demonstrated non-inferiority between groups. Thus, the 2 products are therapeutically similar.

Concepts: Asthma, Relative risk, Dry powder inhaler, Inhaler, Nebulizer, Phase IV, Salmeterol, Fluticasone/salmeterol


To assess the literature that evaluates how variations in metered-dose inhaler (MDI) technique affect lung distribution for inhaled corticosteroids (ICSs) formulated as MDI suspensions and solutions.

Concepts: Asthma, Metered-dose inhaler, Dosage forms, Inhaler


Abstract Background: In pulmonary medicine, aerosolization of substances for continuous inhalation is confined to different classes of nebulizers with their inherent limitations. Among the unmet medical needs is the lack of an aerosolized surfactant preparation for inhalation by preterm neonates, to avoid the risks associated with endotracheal intubation and surfactant bolus instillation. In the present report, we describe a high-concentration continuous powder aerosolization system developed for delivery of inhalable surfactant to preterm neonates. Methods: The developed device uses a technique that allows efficient aerosolization of dry surfactant powder, generating a surfactant aerosol of high concentration. In a subsequent humidification step, the heated aerosol particles are covered with a surface layer of water. The wet surfactant aerosol is then delivered to the patient interface (e.g., nasal prongs) through a tube. Results: The performance characteristics of the system are given as mass concentration, dose rate, and size distribution of the generated aerosol. Continuous aerosol flows of about 0.84 L/min can be generated from dry recombinant surfactant protein-C surfactant, with concentrations of up to 12 g/m(3) and median particle sizes of the humidified particles in the range of 3 to 3.5 μm at the patient interface. The system has been successfully used in preclinical studies. Conclusion: The device with its continuous high-concentration delivery is promising for noninvasive delivery of surfactant aerosol to neonates and has the potential for becoming a versatile disperser platform closing the gap between continuously operating nebulizers and discontinuously operating dry powder inhaler devices.

Concepts: Childbirth, Concentration, Milk, Intubation, Aerosol, Dosage forms, Inhaler, Aerosol spray


Introduction: Computational fluid dynamics (CFD) has recently seen increased use in the design of pharmaceutical inhalers. The use of CFD in the design of inhalers is made difficult by the complex nature of aerosol generation. At present, CFD has provided valuable insight into certain aspects of inhaler performance, though limitations in computational power have prevented the full implementation of numerical methods in the design of inhalers. Areas covered: This review examines the application of CFD in the design of aerosol drug delivery technologies with a focus on pressurized metered-dose inhalers (pMDI), nebulizers and dry powder inhalers (DPIs). Challenges associated with the application of CFD in inhaler design are discussed along with relevant investigations in the literature. Discussions of discrete element modeling (DEM) and the simulation of pharmaceutical aerosol dispersion are included. Expert opinion: The extreme complexity of coupled fluid and aerosol dynamics associated with aerosol generation has somewhat limited the use of CFD in inhaler design. Combined CFD–DEM simulations provide a useful tool in the design of DPIs, though aerosol generation in pMDIs and nebulizers has eluded CFD modeling. The most beneficial use of CFD typically occurs when concurrent CFD and experimental analyses are performed, significantly enhancing the knowledge provided by experiment alone.

Concepts: Fluid mechanics, Computer simulation, Computational fluid dynamics, Metered-dose inhaler, Navier–Stokes equations, Dry powder inhaler, Inhaler, Nebulizer