Study Objectives: A nasopharyngeal seal of the velopharyngeal port is important during swallowing and speaking.An acoustic leak through an open velopharyngeal port has also been reported as a source for overestimations of acoustic pharyngograms.Quantitative data on the effects of the size of the acoustic leak on the pharyngogram has not been published.The current exploratory in vitro study was designed to measure the effects of increasing sizes of a nasopharyngeal acoustic leak on the pharyngogram.Methods: A plastic cast of the human upper airway constructed from a postmortem anatomic casting without a nasal cavity was used in the study.Acoustic leaks through a velopharyngeal port, created ~9 cm from the mouth, were mimicked using 12 different sizes of an open velopharyngeal port with areas ranging from 7.1 mm 2 to 1.54 cm 2 .Nasal cavities of either 20 mL or 30 mL were attached to the open velopharyngeal port.Acoustic pharyngometry was used to measure the size of the cast and the nasal cavities per each open velopharyngeal port size in terms of cross-sectional areas (CSA1-2) and volume (area under the curve; AUC1-3). Results:The effect of the size of the acoustic leak was statistically significant for all CSAs (P<0.0001) and AUCs (P<0.0001),whereas the effect of the acoustic leak with addition of the nasal cavities was statistically significant only for CSA2 (P<0.0001),AUC2 (P<0.0001), and AUC3 (P<0.0001).Conclusion: An acoustic leak through an open velopharyngeal port created an overestimation of the volume of the upper airways as displayed on the pharyngogram.Even small acoustic leaks seemed to have an effect on the pharyngogram.The main effect of the open velopharyngeal port appeared to occur distal to the acoustic leak and was influenced by both the size of the acoustic leak, and the volume of area being leaked into.

Introduction: The mouth, the pharynx and the larynx are potential sites of aerosol deposition in the upper airway during inhalation of aerosolized drugs. The right angle bend of the lumen at the back of the mouth, the position of the tongue, the variable size and shape of the lumen in the pharynx and the larynx, and the breathing pattern could increase aerosol deposition in the upper airway and decrease lung deposition.Areas covered: In this review, the anatomy of the upper airway from the oral cavity to the glottis and the impact of mandibular protrusion and incisal opening on the size of the upper airway are highlighted. In addition, the impact of inhalation maneuvers, inhaler mouthpiece geometries and a stepped mouthpiece on the size of the upper airway are discussed.Expert opinion: The structure of the upper airway lumen does not have a fixed cross sectional area and is susceptible to both constriction and distension during inhalation. The size of the upper airway can be enlarged through mandibular protrusion and/or incisal opening which might decrease aerosol deposition in the upper airway and increase lung deposition.

BACKGROUND:Valved holding chambers (VHCs) are used in children to deliver pressurized metered dose inhalers (pMDI). In vitro data suggest that uncoordinated use decreases the amount of drug available for inhalation. We hypothesize that in an ex vivo study, the coordinated maneuver will deliver more drug than the uncoordinated one. PATIENTS AND METHODS:Thirty-two clinically stable asthmatic children, ages 5-8 years, completed the study. An aerosol filter was interposed between a small-volume nonelectrostatic VHC and a mouthpiece to capture the drug emitted by one puff of Flovent® 220 mcg during tidal breathing. Inhalation and actuation parameters were measured by an electronic monitor, and the number of breaths required to empty the VHC was calculated. Subjects completed three coordinated and three uncoordinated (actuation at the beginning of inhalation and exhalation, respectively) runs in random order. Drug content from the filter and VHC was measured by high-performance liquid chromatography and expressed as percentage of emitted dose. RESULTS:[mean (99% confidence interval)] Filter dose was higher during coordinated technique 46% (43%-50%) than during uncoordinated technique 41% (37%-44%) (p < 0.001). Peak inspiratory flow and tidal volume were 23.2 L/min (21.3-25.1 L/min) and 281 mL (251-311 mL), respectively. Subjects required three breaths to empty the VHC in 96% of the tests. CONCLUSIONS:Actuating the pMDI into a small-volume nonelectrostatic VHC during exhalation reduced by 11% the amount of fluticasone captured at the exit of the VHC. Asthmatic children (5-8 years old) need three or less breaths to empty the small-volume VHC (NCT01714063).

Introduction: Nebulizers are a common device choice for use when developing a new drug product, but the range of nebulizer devices available can make it difficult to select the right device. Increasingly, companies are only able to promote a drug with the device that was used during the development program; therefore, choosing the best device at an early stage is important in order to achieve commercial success. Selecting a device that is inappropriate for the intended drug can result in poor drug delivery from the nebulizer to the patient, which would have obvious implications for the development program. As device performance varies, it is important to ensure that the most appropriate device is chosen for the intended drug to ensure optimal drug delivery to the patient population.Areas covered: In this review, the types of nebulizer devices available are highlighted, and the factors that should be taken into consideration when selecting the most appropriate device for a new drug are discussed. The review is broadly divided into drug, device, patient and trial characteristics.Expert opinion: Efficient nebulizer devices that combine electronic monitoring capabilities as a form of telehealth are likely to provide superior drug delivery to patients and accurate clinical trial data. Their use in adaptive clinical trials may help to vastly reduce the time and costs associated with achieving drug approval.

BACKGROUNDPressurized metered dose inhalers (pMDIs), combined with a valved holding chamber (VHC) and facemask, are often used for young asthmatic children. When using a VHC with facemask, a tight seal between the facemask and the patient's face is crucial for efficient pulmonary aerosol delivery. Realistic parameters for in vitro bench testing are not well known. A custom instrumented OptiChamber Diamond VHC, known as the Facemask Datalogger, was developed to measure the real-time application of force and the air flow through the VHC and facemask.METHODSThirty asthmatic children aged 1-4 years from the Kinderhaven outpatient clinic, who were prescribed a pMDI/VHC with facemask for regular use, were included in the study. Using the Facemask Datalogger, the parent applied the facemask to the face of the child during normal tidal breathing, and force and flow were recorded. This was repeated three times. A video of the procedure was made and scored on cooperation (scale of 1-5).RESULTSMean application force was 4 N (± 1.5) equal to 411 g (± 156) when expressed as a weight equivalent; intrasubject variability in application force was 23% (± 23); intersubject variability in application force was 39%; time needed to empty the VHC was 4.5 sec (± 2.9); breaths needed to empty the VHC were 2.9 (± 1.1); and mean cooperation score was 4.3 (± 0.8). Age was correlated with time (r=-0.49; p=0.006) and breaths needed to empty the VHC (r=-0.75; p<0.001), and observer cooperation score (r=0.65; p<0.001).CONCLUSIONSThe Facemask Datalogger is useful for measuring application force and air flow in vivo. Mean application force was lower than assumed in other studies. Older children emptied the VHC faster, with fewer breaths and better cooperation. The data from this study can be used in the future development and testing of new facemasks and VHCs.

Spacers and valved holding chambers (VHCs) are pressurized metered dose inhaler (pMDI) accessory devices, designed to overcome problems that patients commonly experience when administering aerosol via a pMDI. Spacers were developed in direct response to patient-related issues with pMDI technique, particularly, poor coordination between actuation and inhalation, and local side-effects arising from oropharyngeal deposition. Current clinical guidelines indicate the need for widespread prescription and use of spacers, but, despite their apparent ubiquity, the devices themselves are, unfortunately, all too commonly "disused" by patients. An understanding of the background from which spacers developed, and the key factors influencing the optimization of the spacer and the later VHC, is crucial to developing an appreciation of the potential of these devices, both contemporary and future, for improving the delivery of pressurized aerosols to patients. This review, informed by a full patent search and an extensive scientific literature review, takes into account the clinical and laboratory evidence, commercial developments, and the sometimes serendipitous details of scientific anecdotes to form a comprehensive perspective on the evolution of spacers, from their origins, in the early days of the pMDI, up to the present day.

BACKGROUNDResearch on the use of a pressurized metered dose inhaler (pMDI) with spacer (pMDI/spacer) in children has indicated oral inhalation via the spacer mouthpiece is more efficient than the combination of oral and nasal inhalation that occurs when a pMDI/spacer is used with a facemask. Changes in pMDI formulations and developments in spacer and facemask designs have highlighted the need for new comparative studies of spacer use, particularly focusing on the age at which children can be taught to transition from use of a pMDI/spacer with facemask to use of the spacer mouthpiece.METHODSTwelve children aged 3-5 years (7 males) with stable asthma were recruited. Of these, 10 children (6 males) completed both arms of the study. A transmission scan of each compliant subject was taken using a 37 MBq (99m)Tc flood source. Actuations (2-3) of a (99m)Tc-radiolabeled albuterol pMDI were administered through an antistatic spacer (OptiChamber Diamond) via either a facemask (medium LiteTouch facemask), or the spacer mouthpiece. The subject's inhalation pattern was simultaneously recorded using a pMDI Datalogger, and narrative data relating to tolerance and compliance were documented. Anterior and posterior planar scintigraphic scans were taken immediately after aerosol administration.RESULTSMean (SD) lung deposition (% total dose) was 18.1 (9.1)% with the facemask and 22.5 (7.9)% with the spacer mouthpiece (p>0.05). Peripheral lung deposition (expressed as peripheral:central (P:C) ratio) was higher in 7 out of 10 children with the facemask compared with the spacer mouthpiece: 1.3 (0.26) vs. 1.2 (0.35); (p=0.11). Head and neck deposition was higher with use of the facemask compared with the spacer mouthpiece: 19.7 (10.6)% vs. 10.8 (5.3)% (p=0.011).CONCLUSIONSLung deposition achieved using the spacer with facemask was higher than previously reported, with a difference of only 4.4% of total dose measured compared to the deposition with mouthpiece. This may be due to a combination of factors including pMDI formulation, and use of an antistatic spacer with a flexible, well-fitting facemask.

The I-neb Adaptive Aerosol Delivery (AAD) System is designed to emit aerosol only during the inspiratory phase of breathing and can be operated in tidal breathing mode (TBM), in which the user breathes in a normal manner during treatment, or target inhalation mode (TIM), in which the user is guided to longer inhalations via feedback from the I-neb AAD system. The I-neb AAD system is equipped with a patient logging system (PLS) to facilitate the analysis of patient breathing by recording data on treatment time and mean inhalation time per breath per treatment. Forty nine patients with cystic fibrosis were enrolled in a 13 week handling study; PLS data was analyzed for 43 of these patients. Each patient9s mean treatment (nebulization) time and inhalation time per breath were calculated for treatments taken in TBM or TIM in order to determine the relationship of these variables. Figure 1. Mean patient treatment times versus mean patient inhalation times The median of patient mean treatment times for TBM and TIM were 291 and 146 s, respectively. The median of patient mean inhalation times were 2.6 and 6.9 s, respectively. Patients with longer inhalation times generally had shorter treatment times and patients using TIM had shorter treatment times than those using TBM. It might therefore be of benefit for patients using TBM to switch to using TIM.

Facemasks establish the vital patient-device interface to facilitate drug delivery from a pressurized metered dose inhaler (pMDI) with an attached valved holding chamber (VHC). Leakage from a VHC facemask seal can reduce the delivered dose. We used two pediatric simulated anatomical models (SAMs, Figure 1 Right) to test the leakage from six VHC facemasks. Testing was conducted using an apparatus which allowed reproducible facemask placement with a constant applied force of 1.9kg. 1 Each facemask with associated VHC (Figure 1 Left) was applied to each SAM in turn. A constant flow of 15 L/min was extracted from the rear of the SAM. The difference (ΔTSI, L/min) between flow into the VHC and flow exiting the SAM was measured using two flow meters (TSI Inc, Shoreview, MN). The vertical location of the SAM in relation to the VHC was altered by 1 mm increments until the minimum ΔTSI (leakage) was found. Figure 1 Left shows the minimum leakage for each VHC/facemask combination with each SAM. Figure 1. Left - Facemask seal leakage (%), Top Right - SAM 0, Bottom Right - SAM 1. There was a wide variation in leakage from different VHC facemasks and also between SAMs. The smallest amount of leakage for both SAMs was seen with the OptiChamber Diamond VHC with LiteTouch facemask. 1) Hsu et al. Proceedings of Respiratory Drug Delivery Europe 2011; www.rddonline.com.

The valved holding chamber (VHC) has been designed to optimize delivery for those using pressurized metered dose inhalers (pMDIs). We tested the effects on delivered dose of increasing delay between pMDI actuation and flow through the VHC, using both anti-static and conventional VHCs. Ten anti-static Diamond (Diamond; Philips Respironics) VHCs, anti-static AeroChamber Plus Z-Stat and conventional AeroChamber Plus (Z-stat and AC Plus; Monaghan Medical Corp.) VHCs were washed and air dried and six HFA albuterol sulfate pMDIs (ProAir HFA, 90 µg albuterol, Teva Specialty Pharmaceuticals LLC) were primed before use. For each run the pMDI was actuated into the VHC, after a delay of 0, 5 or 10 s flow through the VHC and attached filter occurred at an extraction flow rate of 5, 15 or 30 L/min for 10 s. The pMDI was actuated 10 times for each of the 10 VHCs of each brand at each delay/flow rate combination. Drug deposits were analyzed using HPLC. Results are presented as coefficient of variation of the delivered doses. The co-efficient of variation was highest for the conventional VHC for all test conditions. Use of an anti-static VHC can minimize variability (improve reproducibility) in delivered dose under in vitro test conditions.

Facemasks serve as a patient-device interface to facilitate drug delivery from a pressurized metered dose inhaler (pMDI) with an attached valved holding chamber (VHC), and are capable of significantly affecting inhalation drug therapy. A novel horizontal test rig designed for the evaluation of facemask performance under simulated conditions was used to measure delivered dose from ProAir HFA pMDIs (108 μg albuterol sulfate/actuation, Teva Specialty Pharmaceuticals LLC). Three brands of VHC-facemask systems were tested: preproduction OptiChamber Diamond (Diamond) VHCs with preproduction LiteTouch facemasks (Philips Respironics), AeroChamber Plus Z Stat (Z Stat) VHCs with ComfortSeal facemasks (Monaghan Medical Corp.), and Vortex VHCs with Spinner Duck facemasks (PARI GmbH). A face replica of a four-year-old child, with a replaceable aerosol filter in the “mouth”, was connected to a breathing simulator (ASL 5000; IngMar Medical Ltd) to simulate a pediatric breathing pattern (Vt=155 mL, f=25 bpm I:E=2:3). Each VHC-facemask system was naturally positioned against the face replica with a constant applied force supplied by a mass of 1.9 kg. Albuterol sulfate was quantified using HPLC after 1, 2, 4 and 8 “breaths” following pMDI actuation. The delivered dose using the Diamond-LiteTouch system, after 1 breath, was significantly higher than the delivered dose using the Z Stat-ComfortSeal or the Vortex-Spinner Duck system after 8 breaths (p

Inhaled bronchodilators and anticholinergics are the mainstay in the management of patients with chronic obstructive pulmonary disease. This study compared the in vitro aerosol characteristics from an HFA ipratropium bromide pMDI (Atrovent, 20 μg ipratropium bromide, Boehringer Ingelheim Ltd) with two anti-static VHCs, a preproduction OptiChamber Diamond (Diamond; Philips Respironics) and an AeroChamber Plus Z-Stat (Z-Stat; Monaghan Medical Corp.) VHC, a conventional AeroChamber Plus (AC+, Monaghan Medical Corp.) VHC, and the pMDI alone. Six pMDIs were primed before use and six of each VHC were washed and air dried. For each run (n) the pMDI was actuated into the VHC or next generation impactor (NGI) (for pMDI alone - tested before and after VHC tests), followed by 20 s extraction at 30 L/min, repeated 10 times. Drug deposits from the NGI were analyzed using HPLC. The Emitted Dose (ED; drug entering the NGI), Fine Particle Dose (FPD; amount of drug ≤ 4.7 μm), Fine Particle Fraction (FPF;% of ED in particles ≤ 4.7 μm), and Mass Median Aerodynamic Diameter (MMAD) were determined using Copley Inhalation Testing Data Analysis Software (CITDAS). The aerosol characteristics were similar between the VHCs and removed significant potential throat deposition compared to the pMDI alone.

The goal of asthma treatment is to prevent exacerbations, achieve daily asthma control and prevent adverse effects with a minimum of medication. In preschoolers, children and adolescents with mild persistent asthma, the most effective therapy remains daily use of low-dose inhaled corticosteroids.1 Why then consider intermittent therapy over maintenance inhaled corticosteroids? The intermittent approach is attractive to patients and families for a variety of reasons, including fear of corticosteroid side effects,2 the erroneous concept that no symptoms equate to no disease3 and ease of compliance with medications administered for symptoms rather than on a daily basis. Indeed, pharmacy records clearly show that most children with asthma infrequently renew their prescriptions for controller medications, suggesting that they may not understand, perceive or agree with the need for daily therapy, despite ongoing healthcare resources utilisation and excess use of rescue β2-agonist.4 This practice is also endorsed by physicians who recommend an asthma controller at the onset of an exacerbation for a short period.4 5 In vogue since the 1990s without, until recently, any supporting evidence, the practice of prescribing intermittent therapy over continuous therapy may have stemmed from: (1) the uncertain benefit of daily inhaled corticosteroids in patients in whom there is diagnostic uncertainty (viral wheeze vs asthma), phenotype hesitation (intermittent vs persistent) or a paucity of evidence for therapy (eg, preschoolers); (2) conflicting evidence regarding the long-term benefit of daily therapy as a disease modifier (eg, lung function, quality of life, airway remodelling)6–8; (3) concerns about side effects of daily inhaled corticosteroids; and (4) in the absence of trials, unconvincing evidence of the harm or lack of efficacy of intermittent therapy. Admittedly, these factors may contribute to the ‘giving-up to poor compliance’ popular approach to avoid the time and energy required to repeatedly convince …

Inhaled bronchodilators and anticholinergics are the mainstay in the management of patients with chronic obstructive pulmonary disease. This study compared the in vitro aerosol characteristics from an HFA ipratropium bromide pMDI (Atrovent, 20 μg ipratropium bromide, Boehringer Ingelheim Ltd) with two anti-static VHCs, a preproduction OptiChamber Diamond (Diamond; Philips Respironics) and an AeroChamber Plus Z-Stat (Z-Stat; Monaghan Medical Corp.) VHC, a conventional AeroChamber Plus (AC+, Monaghan Medical Corp.) VHC, and the pMDI alone. Six pMDIs were primed before use and six of each VHC were washed and air dried. For each run (n) the pMDI was actuated into the VHC or next generation impactor (NGI) (for pMDI alone - tested before and after VHC tests), followed by 20 s extraction at 30 L/min, repeated 10 times. Drug deposits from the NGI were analyzed using HPLC. The Emitted Dose (ED; drug entering the NGI), Fine Particle Dose (FPD; amount of drug ≤ 4.7 μm), Fine Particle Fraction (FPF;% of ED in particles ≤ 4.7 μm), and Mass Median Aerodynamic Diameter (MMAD) were determined using Copley Inhalation Testing Data Analysis Software (CITDAS). Table 1. Results: Mean (Standard Deviation) Device ED (μg) FPD (μg) FPF (%) MMAD (μm) pMDI alone (n=12) 16.5 (0.9) 5.7 (0.6) 34.6 (4.7) 0.87 (0.05) pMDI with Diamond VHC (n=6) 8.2 (0.6) 6.1 (0.9) 74.3 (6.7) 0.92 (0.04) pMDI with Z-Stat VHC (n=6) 8.6 (0.7) 6.3 (1.1) 73.0 (7.9) 0.87 (0.02) pMDI with AC+ VHC (n=6) 7.4 (1.0) 5.2 (0.9) 69.6 (3.9) 0.87 (0.02) The aerosol characteristics were similar between the VHCs and removed significant potential throat deposition compared to the pMDI alone.