Use Of Dry Powder Inhalers Research Articles

Different Carriers for Use in Dry Powder Inhalers: Characteristics of Their Particles.

In contemporary times, there has been a rise in the utilization of dry powder inhalers (DPIs) in the management of pulmonary and systemic diseases. These devices underwent a swift advancement in terms of both the equipment utilized and the formulation process. In this review, the carrier physicochemical characteristics that influence DPI performance are discussed, focusing its shape, morphology, size distribution, texture, aerodynamic diameter, density, moisture, adhesive and detachment forces between particles, fine carrier particles, and dry powder aerosolization. To promote the deposition of the active principal ingredient deep within the pulmonary system, advancements have been made in enhancing these factors and surface properties through the application of novel technologies that encompass particle engineering. So far, the most used carrier is lactose showing some advantages and disadvantages, but other substances and systems are being studied with the intention of replacing it. The final objective of this review is to analyze the physicochemical and mechanical characteristics of the different carriers or new delivery systems used in DPI formulations, whether already on the market or still under investigation. [Figure: see text].

Dry Powder Inhaler Use in Primary School Aged Children with Asthma: A Systematic Review

ObjectiveAsthma is the most common chronic disease in children. Dry powder inhalers (DPI) are effective for medication delivery in adults and adolescents, and provide a lower environmental footprint and more portability when compared to metered dose inhaler (MDI) with spacer. They require specific technique, and it is necessary to ascertain whether they can be used in younger age groups. We aimed to assess evidence regarding whether primary school aged (5–11 years) children can use DPI with adequate technique both during stable and acute asthma.DesignOvid MEDLINE, Embase and PubMed were searched for studies assessing DPI use in children aged 5–11 years with asthma or wheeze. Results of studies were synthesised by study design and outcome measure.ResultsThirty-eight studies were identified for analysis. These were analysed in three groups: (1) 25 studies assessing children's ability to use DPI by peak inspiratory flow measurement, (2) 10 studies assessing children's ability to use DPI by physician assessment, and (3) three studies measuring efficacy of DPI compared to gold standard (MDI with spacer). Five studies included children during acute exacerbations.ConclusionThe majority of primary school aged children have the ability to use a DPI with adequate training, support and practice. Some younger children may have difficulties, and clinician assessment and ongoing review is crucial in determining which children are likely to benefit from a DPI. Consistent correct use and adherence remains a challenge, but this is also an issue with MDI plus spacer and does not appear to be significantly worse with DPI. Evidence of the use of DPI during acute illness is limited, and more studies are required in this setting.

Suboptimal peak inspiratory flow rate: a noticeable risk factor for inhaler concordance in patients with chronic airway diseases

BackgroundInhaler concordance and the peak inspiratory flow rate (PIFR) are important determinants of treatment effects in patients with chronic airway diseases. Adequate PIFR is required for driving aerosol medication into...

Co-Delivery of a High Dose of Amphotericin B and Itraconazole by Means of a Dry Powder Inhaler Formulation for the Treatment of Severe Fungal Pulmonary Infections.

Over the past few decades, there has been a considerable rise in the incidence and prevalence of pulmonary fungal infections, creating a global health problem due to a lack of antifungal therapies specifically designed for pulmonary administration. Amphotericin B (AmB) and itraconazole (ITR) are two antifungal drugs with different mechanisms of action that have been widely employed in antimycotic therapy. In this work, microparticles containing a high dose of AmB and ITR (20, 30, and 40% total antifungal drug loading) were engineered for use in dry powder inhalers (DPIs) with an aim to improve the pharmacological effect, thereby enhancing the existing off-label choices for pulmonary administration. A Design of Experiment (DoE) approach was employed to prepare DPI formulations consisting of AmB-ITR encapsulated within γ-cyclodextrin (γ-CD) alongside functional excipients, such as mannitol and leucine. In vitro deposition indicated a favourable lung deposition pattern characterised by an upper ITR distribution (mass median aerodynamic diameter (MMAD) ~ 6 µm) along with a lower AmB deposition (MMAD ~ 3 µm). This offers significant advantages for treating fungal infections, not only in the lung parenchyma but also in the upper respiratory tract, considering that Aspergillus spp. can cause upper and lower airway disorders. The in vitro deposition profile of ITR and larger MMAD was related to the higher unencapsulated crystalline fraction of the drug, which may be altered using a higher concentration of γ-CD.

Identifying critical inhalation technique errors in Dry Powder Inhaler use in patients with COPD based on the association with health status and exacerbations: findings from the multi-country cross-sectional observational PIFotal study

BackgroundCorrect inhaler use depends on a complex interplay of factors, including device preparation and generating sufficient inspiratory flow. It is currently unknown which inhalation technique errors can be considered critical in Chronic Obstructive Pulmonary Disease (COPD) patients on Dry Powder Inhaler (DPI) maintenance therapy.ObjectiveTo investigate the association between inhalation technique errors and health status or exacerbations in patients with COPD. Additionally, the association between the number of errors and COPD outcomes was determined.MethodsThe PIFotal study is a cross-sectional multi-country observational study in a primary care setting, including 1434 COPD patients aged ≥ 40 years (50.1% female; mean age 69.2 yrs) using a DPI for their maintenance therapy. Inhalation technique was video recorded and scored by two independent researchers using inhaler-specific checklists. Health status was assessed with two questionnaires; the Clinical COPD Questionnaire (CCQ) and the COPD Assessment Test (CAT). The number of moderate and severe exacerbations in the past 12 months was recorded. Critical errors were identified based on their association with health status or exacerbations through multi-level prediction models adjusted for identified confounding.ResultsErrors in inhalation technique steps ‘Breathe in’, ‘Hold breath’, and ‘Breathe out calmly after inhalation’ were significantly associated with poorer CCQ and CAT outcomes and thus deemed critical. None of the errors were significantly associated with moderate exacerbations. Patients with errors ‘Preparation’, ‘Hold inhaler in correct position during inhalation’, and ‘Breathe in’ had significantly more severe exacerbations, and therefore these errors were also deemed critical. 81.3% of patients with COPD made at least one critical error. Specific combinations of errors were associated with worse outcomes. The more inhalation technique errors identified, the poorer the health status and the higher the exacerbation rate.ConclusionIn this study, we identified multiple critical inhalation technique errors in COPD patients using DPIs each associated with poorer outcomes. Explorative analysis revealed that specific combinations of errors may be of clinical relevance, especially those related to the inhalation manoeuvre. COPD outcomes worsened with increasing error count. These results warrant further prospective longitudinal studies to establish the effect of correcting these errors on COPD control.Trial registrationhttps://clinicaltrials.gov/ct2/show/NCT04532853 (31/08/2020)

The impact of possible improper use on the performance in vitro of NEXThaler in comparison with Ellipta inhaler

The correct use of dry powder inhalers by the patients is essential to ensure effective treatment and management of the disease. The purpose of the work was to assess the consequence of inhaler misuse in terms of emitted dose and aerodynamic parameters. One reservoir multidose device (Foster-NEXThaler®) and one pre-dosed device (Relvar-Ellipta®), both sharing the “open, inhale and close” procedure, were the subject of the study. NEXThaler activated at different degrees of inclination showed a consistent dose delivery for both the drugs included in the formulation (beclometasone dipropionate/formoterol fumarate). Contrary, Ellipta showed a decrease of the emitted dose for both fluticasone furoate (FluF) and vilanterol trifenatate (VT) when the device was operated facing downward (–14% at 45° and –22% at 90°). Similarly, the delivered dose of NEXThaler was unaffected by an accidental fall, while Ellipta released FluF and VT doses 50% lower than control values. The presence of the dose protector in NEXThaler offers the advantage of retaining the powder if the inhaler is subjected to incorrect manipulations. Both products proved to be reliable in double activation. Finally, simulation exhalation conditions impaired, although not significantly, the aerodynamic profile of the two products.

Clinical recommendations for dry powder inhaler use in the management of COPD in primary care

Over 1400 patients using dry powder inhalers (DPIs) to deliver COPD maintenance therapies were recruited across Europe and Australia. Their peak inspiratory flow (PIF) was measured, inhaler technique was observed, and adherence to treatment assessed. From relating the findings with patient health status, and thereby identifying critical errors, key clinical recommendations for primary care clinicians were determined, namely – measure PIF before prescribing a DPI to ensure inhalation manoeuvre ability is well-matched with the device. Some patients could benefit from inhalation training whereas others should have their DPI changed for one better suited to their inspiratory ability or alternatively be prescribed an active device (such as a soft mist inhaler or pressurized metered dose inhaler). Observing the inhalation technique was valuable however this misses suboptimal PIF (approaching one fourth of patients with a satisfactory observed manoeuvre had a suboptimal PIF for their DPI). Assess adherence as deliberate non-adherence can point to a mismatch between a patient and their inhaler (deliberate non-adherence was significantly associated with PIFs below the minimum for the DPI). In-person observation of inhalation technique was found to be inferior to video rating based on device-specific checklists. Where video assessments are not possible, observation training for healthcare professionals would therefore be valuable particularly to improve the ability to identify the critical errors associated with health status namely ‘teeth and lips sealed around mouthpiece’, ‘breathe in’ and ‘breathing out calmly after inhalation’. However, it is recommended that observation alone should not replace PIF measurement in the DPI selection process.Trial registration:https://clinicaltrials.gov/ct2/show/NCT04532853.

Getting the Most out of Spirometry: A Tool to Guide Dry Powder Inhaler Use.

Dry powder inhaler (DPI) use requires sufficient peak inspiratory flow over the DPI internal resistance (PIFR). We examined whether spirometric peak inspiratory flow (PIFspiro) could serve to predict PIFR in patients with obstructive lung disease. Thirty healthy nonsmokers and 140 stable outpatients (70 COPD, 70 asthma) performed spirometry according to the 2019 ERS/ATS spirometry update, yielding PIFspiro. Using a PIFR measurement device with varying orifices, all subjects' PIFR values were recorded for 5 predefined resistance levels, characterized by 5 orifice cross sections (SR). A test group including all healthy subjects, 30 of the asthma, and 30 of the COPD patients was used to establish the relationship between PIFR and both PIFspiro and SR by multiple regression. A validation group including the remaining 40 asthma and 40 COPD patients, served to verify whether their predicted PIFR value corresponded to the measured PIFR for each resistance level. The asthma (FEV1 = 78 ± 17 [SD] %pred) and COPD (FEV1 = 46 ± 17 [SD] %pred) patients under study had varying airway obstruction. In the test group, PIFR could be predicted by ln[PIFspiro] (p < 0.0001), SR (p < 0.0001), and SR2 (p = 0.006), with an adjusted R2 = 0.71. In the validation group, estimated PIFR did not significantly differ from measured PIFR (p > 0.05 for the 5 resistance levels). We propose a simple method to predict PIFR for a range of common DPI resistances, based on the device characteristics and on the patient's characteristics reflected in PIFspiro. As such, routine spirometry can serve to estimate a patient's specific PIFR without the need for additional testing.

Evaluating metered dose inhaler and dry powder inhaler use technique among bronchial asthma and COPD patients attending tertiary health care centre in South India

Background: Inhaler is a device used by patients who have chronic respiratory illness. Inhaled medication is directly deposited in the lungs, which is its site of action. Improper use of inhalers can lead to worsening of disease, over medication and side effects including oral candidiasis. This study aims to evaluate the inhaler use technique.Methods: A hospital based cross sectional study was conducted among patients who were using inhalers for one year or more attending respiratory medicine OPD using pretested semi-structured questionnaire.Results: The majority of 81 patients were MDI users. Only 8.64% of them performed all the steps according to NIH guidelines regarding proper technique of inhaler use properly. Among the 39 patients who used dry powder Inhaler, 33% correctly performed all the steps according to the guidelines.Conclusions: Only a low proportion of patients properly performed the steps in the technique of using inhalers. Improper use of inhalers leads to poor efficacy of the treatment. So health care providers should take measures to ensure that the patients on inhalers are aware of the proper technique and are following the steps in using inhalers correctly.

Surface modification strategies for high-dose dry powder inhalers

There is a growing interest in the use of dry powder inhalers (DPIs) for administering high-dose drugs with low potency to the lungs as carrier-free formulations to treat both local pulmonary and systemic diseases. The main purpose of particle engineering and formulation design in the development of high-dose DPIs without carrier is to reduce the cohesive property of the particles and overcome the large inter-particulate interaction while enhancing powder dispersion and lung delivery upon inhalation and maintaining stability without agglomeration during storage. In particular, the cohesive property of high-dose DPIs can induce several physiological and physicochemical problems that must be improved. This review describes various particle surface modification methods, including sophisticated particle engineering (such as micronization) and formulation techniques, which are utilized to overcome the problems associated with high-dose DPIs. Currently, changing the cohesive property of particles through various micronization processes and improving the surface properties of particles through co-processing with limited excipients have been mainly used as efficient methods for particle surface modification. Using these technological principles, novel approaches have been attempted to develop inhalable drug particles, such as high-dose antibiotics and high-value biopharmaceuticals. The research on high-dose DPIs has expanded widely, and consequently, the drugs that received recent regulatory approvals have been successful based on the research results. Thus, it is expected that the next generation of DPIs will be safer and have higher therapeutic efficacy beyond the limitations of traditional high-dose DPIs.

Inspiratory flow patterns with dry powder inhalers of low and medium flow resistance in patients with pulmonary arterial hypertension.

Inhalation profiles to support use of dry powder inhalers for drug delivery in patients with pulmonary arterial hypertension have not been reported. We aimed to evaluate the inspiratory flow pattern associated with low and medium flow resistance dry powder inhaler devices (RS01-L and RS01-M, respectively) in patients with pulmonary arterial hypertension. This single-center study enrolled patients with pulmonary arterial hypertension associated with connective tissue disease (n = 10) and idiopathic pulmonary arterial hypertension (n = 10) to measure the following inhalation parameters: inspiratory effort (kPa), peak inspiratory flow rate (L/min), inhaled volume (L), and flow increase rate (L/s2) using the two devices. We identified a trend toward higher mean pulmonary artery pressure in the idiopathic pulmonary arterial hypertension group (50 ± 13 mmHg vs. 40 ± 11 mmHg in pulmonary arterial hypertension associated with connective tissue disease; p = 0.077). On average, peak inspiratory flow rate was higher with RS01-L vs. RS01-M (84 ± 19.7 L/min vs. 70.4 ± 13.2 L/min; p = 0.015). In the overall group, no differences between RS01-L and RS01-M were observed for inhaled volume, inspiratory effort, or flow increase rate. Inhaled volume with RS01-L was higher in pulmonary arterial hypertension associated with connective tissue disease vs. idiopathic pulmonary arterial hypertension patients: 1.6 ± 0.4 L vs. 1.3 ± 0.2 L; p = 0.042. For the RS01-L, inhaled volume correlated with forced expiratory volume in one second (r = 0.460, p = 0.030) and forced vital capacity (r = 0.507, p = 0.015). In patients with pulmonary arterial hypertension associated with connective tissue disease using RS01-L, both inspiratory effort and flow increase rate were highly correlated with pulmonary vascular compliance (r = 0.903, p = 0.0001 and r = 0.906, p = 0.0001; respectively); while with RS01-M, inspiratory effort was highly correlated with pulmonary vascular compliance (r = 0.8, p = 0.001). Our data suggest that the use of RS01-L and RS01-M dry powder inhaler devices allowed adequate inspiratory flow in pulmonary arterial hypertension patients. The correlation between flow increase rate and pulmonary vascular compliance in pulmonary arterial hypertension associated with connective tissue disease deserves further investigation.

In-vitro and particle image velocimetry studies of dry powder inhalers.

Inhalation drug delivery has seen a swift rise in the use of dry powder inhalers (DPIs) to treat chronic respiratory conditions. However, universal adoption of DPIs has been restrained due to their low efficiencies and significant drug losses in the mouth-throat region. Aerosol efficiency of DPIs is closely related to the fluid-dynamics characteristics of the inhalation flow generated from the devices, which in turn are influenced by the device design. In-vitro and particle image velocimetry (PIV) have been used in this study to assess the aerosol performance of a model carrier formulation delivered by DPI devices and to investigate their flow characteristics. Four DPI device models, with modification to their tangential inlets and addition of a grid, have been explored. Similar aerosol performances were observed for all four device models, with FPF larger than 50%, indicating desirable lung deposition. A high swirling and recirculating jet-flow emerging from the mouthpiece of the DPI models without the grid was observed, which contributed to particle deposition in the throat. DPI models where the grid was present showed a straightened outflow without undesired lateral spreading, that reduced particle deposition in the throat and mass retention in the device. These findings demonstrate that PIV measurements strengthen in-vitro evaluation and can be jointly used to develop high-performance DPIs.

An Audio-Based Method for Assessing Proper Usage of Dry Powder Inhalers

Critical technique errors are very often performed by patients in the use of Dry Powder Inhalers (DPIs) resulting in a reduction of the clinical efficiency of such medication. Those critical errors include: pure inhalation, non-arming of the device, no exhalation before or after inhalation, and non-holding of breath for 5–10 s between inhalation and exhalation. In this work, an audio-based classification method that assesses patient DPI user technique is presented by extracting the the non-silent audio segments and categorizing them into respiratory sounds. Twenty healthy and non-healthy volunteers used the same placebo inhaler (Bretaris Genuair Inhaler) in order to evaluate the performance of the algorithm. The audio-based method achieved an F1-score of 89.87% in classifying sound events (Actuation, Inhale, Button Press, and Exhale). The significance of the algorithm lies not just on automatic classification but on a post-processing step of peak detection that resulted in an improvement of 5.58% on the F1-score, reaching 94.85%. This method can provide a clinically accurate assessment of the patient’s inhaler use without the supervision of a doctor.

Simulations of the deposition of pharmaceutical aerosols in the human respiratory tract by dry powder inhalers (DPIs)

Investigation of pharmaceutical aerosol deposition in the human respiratory tract is an important topic because it enhances knowledge regarding the effective treatment of lung diseases. Herein, deposition in the human respiratory tract produced by the use of Dry Powder Inhalers (DPIs) was modeled for an adult male. A modified version of the model named Exposure Dose Model 2 (ExDoM2) was used where simulations incorporated both monodisperse and polydisperse aerosols. The impact of breath holding and mouthpiece diameter was also examined. The results revealed that the larger the aerodynamic diameter, the greater the deposition in the extrathoracic region. On the contrary, higher deposition of polydisperse particles in the tracheobronchial and alveolar-interstitial region was observed for particles with aerodynamic diameter 2–4 μm. In the extrathoracic region, deposition increased with a decrease in the mouthpiece diameter. However, its effect is negligible for particles approximately <1 μm in the tracheobronchial and alveolar-interstitial regions. For bigger particles, an increase in mouthpiece diameter resulted in an increase of the deposition. Similar findings were obtained for monodisperse particles. In addition, the results showed that breath holding increases the deposition in the lungs for all mouthpiece diameters and Mass Median Aerodynamic Diameters (MMADs), which confirms the medical recommendations of breath holding after inhalation of pharmaceutical aerosols through DPIs for more effective treatment of lung diseases. Finally, the user of the modified version of ExDoM2 has the capability to modify the parameters of the model for a more representative/realistic scenario. Future objectives include simulations that adopt the effect of particle properties (density and shape factor) and other parameters (such as the tidal volume), as well as simulations incorporating deposition using realistic input data (MMAD and standard deviation sg).

Spirometry Measurement of Peak Inspiratory Flow Identifies Suboptimal Use of Dry Powder Inhalers in Ambulatory Patients with COPD.

Determine the prevalence of suboptimal peak inspiratory flow rate (PIFR) and associated patient characteristics and compare PIFR measurements obtained with spirometry and In-Check DIAL® device in ambulatory patients with COPD. Patients underwent PIFR measurement with In-Check DIAL® device and pulmonary function testing with calibrated equipment. Group characteristics and lung function were compared for patients with suboptimal (≤ 60 L/min) and optimal (> 60 L/min) PIFR. Receiver operating curve analysis determined the best maximal forced inspiratory flow (FIF max) value in identifying optimal PIFR by gender and height. From July 1, 2016 to January 31, 2018, a total of 303 patients with chronic obstructive pulmonary disease (COPD) had PIFR and pulmonary function measurements. Group mean age was 65.5 ± 11.3 years with equal gender distribution. Suboptimal PIFR was observed in 61 (20.1%) patients. A significant correlation was observed between PIFR and FIF max, inspiratory capacity and residual volume (RV) to total lung capacity (TLC) ratio. In the suboptimal PIFR group, mean FIF max measured by spirometry was significantly less compared with the optimal PIFR group; 178.5 ± 56.9 L/min and 263.4 ± 89.9 L/min, respectively (p<0.0001). Receiver operator curve analysis of FIF max to identify an optimal PIFR yielded an area under the curve of 0.79. Males < 65 inches had a suboptimal PIFR in 16.7 % of the male cohort, while females < 65 inches had a suboptimal PIFR in 27.4 % of the women. Suboptimal PIFR was present in 1 in 5 stable patients with COPD and was more frequent in short statured females. Spirometry determined FIF max was associated with PIFR based on gender and height.

Analysis of Patient Characteristics and Peak Inspiratory Flow Rates in Three Phase 3 Trials of Nebulized Glycopyrrolate in Moderate to Very Severe COPD

SESSION TITLE: COPD 3 SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, November 1, 2017 at 01:30 PM - 02:30 PM PURPOSE: Successful use of dry powder inhalers requires adequate inspiratory flow; however, many COPD patients have reduced peak inspiratory flow rates (PIFR). Identifying patients with low PIFR may help with device selection; nebulizers rely on tidal breathing so are less affected by inspiratory flow. This post-hoc analysis investigated the relationship between baseline PIFR and patient characteristics in three Phase 3 trials of nebulized glycopyrrolate (GLY) administered via the eFlow® Closed System nebulizer (PARI Pharma, Germany) in moderate-to-very-severe COPD. METHODS: Data from two replicate 12-week, placebo-controlled trials of nebulized GLY were pooled. PIFR was measured using the ‘free-flow’ resistance setting on the In-Check DIAL. Data from a 48-week safety study of nebulized GLY vs tiotropium (TIO; Handihaler) were also analyzed. PIFR was measured using the ‘Handihaler’ resistance setting on the In-Check DIAL. Subjects were stratified by PIFR (<60 and ≥60 L/min) and analyzed by age, gender, height and weight, all previously shown to correlate with PIFR (Mahler et al. JAMPDD 2013;26:174-9). RESULTS: Data from 1291 subjects in the 12-week placebo-controlled studies were analyzed. At baseline, the forced expiratory volume in one second (FEV1) % predicted was 51.7%, and 31.1% of subjects were receiving long-acting β2-agonists (LABA). 331 (25.6%) subjects had PIFR <60 L/min and 960 (74.4%) PIFR ≥60 L/min. In both groups, median age was 63 years and 9.7% of subjects were ≥75 years old. The percentage of females was slightly higher in the <60 L/min group than the ≥60 L/min group (45.6% vs 43.4%). Median height (171 cm), and weight (81 kg), did not differ between PIFR groups. GLY improved lung function in subjects irrespective of PIFR and adverse event rates did not differ between groups. Data from 1072 subjects in the 48-week safety study were analyzed. At baseline, FEV1 % predicted was 51.3% and 42.3% of subjects were receiving LABA. 363 (33.9%) subjects had PIFR <60 L/min and 709 (66.1%) PIFR ≥60 L/min. Median age was 64 years and 63 years in the <60 L/min and ≥60 L/min groups, respectively. The percentage of subjects ≥75 years was higher in the <60 L/min group (11.3%) than in the ≥60 L/min group (8.7%). There was a greater percentage of females in the <60 L/min group (48.8%) than in the ≥60 L/min group (41.3%). Median height was 169 cm in the <60 L/min group and 170.1 cm in the ≥60 L/min group, and the corresponding weights were 80.7 kg and 82 kg. GLY and TIO improved lung function in subjects irrespective of PIFR and adverse event rates did not differ between groups. CONCLUSIONS: In the analysis using the resistance-free In-Check DIAL, PIFR was largely unaffected by age, gender, height and weight. In the analysis using the ‘Handihaler’ resistance setting, PIFR <60 L/min was associated with female gender, age ≥75 years, and, to a lesser extent, smaller body size. CLINICAL IMPLICATIONS: Certain patient characteristics may be related to PIFR, which could be useful to consider when selecting an appropriate inhalation device. Increasing the resistance on the In-Check DIAL may reveal correlations between patient characteristics and PIFR that are not observed on a resistance-free setting. DISCLOSURE: Donald Mahler: Consultant fee, speaker bureau, advisory committee, etc.: Sunovion Pharmaceuticals Inc., Consultant fee, speaker bureau, advisory committee, etc.: Boehringer Ingelheim Barry Price: Employee: Sunovion Pharmaceuticals Inc. Robert Tosiello: Employee: Sunovion Pharmaceuticals Inc. Sanjay Sharma: Employee: Sunovion Pharmaceuticals Inc. Abstract describes analysis from Phase 3 trials of nebulized glycopyrrolate in COPD (not currently approved)

Prerequisites for a dry powder inhaler for children with cystic fibrosis

Correct inhalation technique is essential for effective use of dry powder inhalers (DPIs), as their effectiveness largely depends on the patient’s inhalation manoeuvre. Children are an especially challenging target population for DPI development due to the large variability in understanding and inspiratory capacities. We previously performed a study in which we determined the prerequisites for a paediatric DPI in a mostly healthy paediatric population, for which we used an empty test inhaler with variable internal airflow resistance and mouthpiece. In the current study we investigated what specifications are required for a DPI for children with cystic fibrosis (CF), for which we expanded on our previous findings. We recorded flow profiles of 35 children with CF (aged 4.7–14.7 years) at three airflow resistances (0.031–0.045 kPa0.5.min.L-1) from which various inspiratory parameters were computed. Obstructions in the mouth during inhalation were recorded with a sinuscope. All children were able to perform a correct inhalation manoeuvre, although video analysis showed that children did not place the inhaler correctly in the mouth in 17% of the cases. No effect was found of medium to high airflow resistance on total inhaled volume, which implies that the whole resistance range tested is suitable for children with CF aged 4–14 years. No effect could be established of either mouthpiece design or airflow resistance on the occurrence of obstructions in the mouth cavity. This study confirms our previous conclusion that the development of DPIs specifically for children is highly desired. Such a paediatric DPI should function well at 0.5 L inhaled volume and a peak inspiratory flow rate of 20 to 30 L/min, depending on the internal airflow resistance. This resistance can be increased up to 0.045 kPa0.5.min.L-1 (medium-high) to reduce oropharyngeal deposition. A higher resistance may be less favourable due to its compromising effect on PIF and thereby on the energy available for powder dispersion.

Peak Inspiratory Flow Rate as a Criterion for Dry Powder Inhaler Use in Chronic Obstructive Pulmonary Disease.

Dry powder bronchodilator devices have an internal resistance. Effective use depends on the patient generating an adequate inspiratory flow to break up the powder packets into particles less than 5-μm in diameter that can be inhaled into the lower respiratory tract. This disaggregation takes place inside the device before the dose leaves the inhaler; this process is increased if the acceleration is fast at the start of inhalation. Peak inspiratory flow depends on an individual's effort along with the strength of the respiratory muscles, which may be compromised in those with chronic obstructive pulmonary disease as a result of lung hyperinflation, hypoxemia, and muscle wasting. A handheld inspiratory flow meter can be used with an adjustable dial to simulate internal resistances of dry powder devices to assess whether a patient can achieve an optimal peak inspiratory flow rate of at least 60 L/min. Observational studies demonstrate that 19 to 78% of stable outpatients with chronic obstructive pulmonary disease and 32 to 47% of inpatients prior to discharge after admission for an exacerbation have a suboptimal peak inspiratory flow rate (<60 L/min). These data suggest that peak inspiratory flow rate should be measured against the simulated resistance of the specific dry powder bronchodilator device prior to prescription. If the peak inspiratory flow rate is less than 60 L/min, the patient may not achieve optimal clinical benefit, and a different delivery system, such as a metered-dose or soft mist inhaler or nebulized therapy, should be considered.

Predictors of correct technique in patients using pressurized metered dose inhalers

BackgroundCorrect inhaler technique is recommended by guidelines for optimum asthma care. The objective of the study is to determine real life predictors of correct pressurized metered dose inhaler (pMDI) technique in Asthma and COPD patients.MethodsTwo hundred eight adult patients aged 18+ from respiratory outpatients (69.2%) and the community on regular pMDI for a diagnosis of Asthma (78.9%) or COPD, were recruited. A questionnaire containing 31 possible predictors was administered and pMDI technique with or without spacer was observed by trained researchers on 12 point steps, of which 4 were considered critical.Results23.1% of patients had no errors in inhaler technique and 32.2% had no critical errors. Patients had a median of 10 correct steps (IQR9-11), and 3(IQR2-4) correct critical steps. Using binary logistic regression the predictors of 10 correct steps were, other healthcare professional (pharmacist, nurse, physiotherapist) explained OR 3.73(1.63–8.54, p = 0.001), male gender 2.70(1.35–5.39, p = 0.004), self-score 1–10 1.21(1.05–1.39, p = 0.007), spacer use 0.38(0.19–0.79, p = 0.007), inhaled steroid 3.71(1.34–10.25, p = 0.01), heart disease 0.31(0.13–0.77, p = 0.01), pneumococcal vaccine 2.48(1.0–6.15, p = 0.043), education level 1–4 1.44(1.00–2.06, p = 0.05) and respiratory physician explained 0–7 times, 1.11(0.99–1.26, p = 0.08). Using ordinal logistic regression, predictors for correct critical steps 0–4, were: technique self-score 1–10 1.2(1.05–1.42, p = 0.006), inhaled corticosteroid use 2.78(1.1–7.31, p = 0.03) and education level 1–4 1.41(1.02–1.95, p = 0.03 Times respiratory physician explained inhaler technique 0–7 1.1(0.98–1.24, p = 0.1), married status 1.55(0.85–2.82, p = 0.15), hypercholesterolaemia 0.52(0.25–1.01, p = 0.054) and male gender 1.76(0.97–3.18, p = 0.06).ConclusionsKnown predictors of correct pMDI use, such as gender and education level were confirmed, while age and concomitant use of dry powder inhaler were not. Pneumococcal vaccination and awareness of steroid side effects were possible novel positive predictors, while the use of a spacer and co-morbidity with heart disease were found to be negative predictors. Patients’ self-assessment correlated well with actual performance. This information may be useful in defining approaches to optimize inhaler techniques which are so susceptible to human error.

Evaluating the sensitivity, reproducibility and flexibility of a method to test hard shell capsules intended for use in dry powder inhalers

Pharmaceutical tests for hard shell capsules are designed for orally administered capsules. The use of capsules in dry powder inhalers is widespread and increasing and therefore more appropriate tests are required to ensure quality and determine if these capsules are fit for purpose. This study aims to determine the flexibility, reproducibility and sensitivity of a quantitative method that is designed to evaluate the puncture characteristics of different capsule shell formulations under different climatic conditions. A puncture testing method was used to generate force displacement curves for five capsule formulations that were stored and tested at two different temperatures (5°C and 19°C). Force-displacement puncture profiles were reproducible for individual capsule shell formulations. The methodology was able to discriminate between capsules produced using different primary materials i.e. gelatin versus hypromellose, as well as more minor changes to capsule formulation i.e. different material grades and excipients. Reduced temperature increased the forces required for capsule puncture however further work is required to confirm its significance. Results indicate the method provides a reproducible and sensitive means of evaluating capsule puncture. Future studies should validate the methodology at different test sites, using different operators and with different capsule shell formulations.