Drug Delivery in Asthmatic Children Following Coordinated and Uncoordinated Inhalation Maneuvers: A Randomized Crossover Trial.

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).

The size and behavior of the human upper airway during inhalation of aerosols.

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.

Factors to consider when selecting a nebulizer for a new inhaled drug product development program.

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.

The evolution of spacers and valved holding chambers.

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.

An instrumented valved holding chamber with facemask to measure application forces and flow in young asthmatic children.

BACKGROUND: Pressurized 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. METHODS: Thirty 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). RESULTS: Mean 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). CONCLUSIONS: The 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.

Lung deposition of 99mTc-radiolabeled albuterol delivered through a pressurized metered dose inhaler and spacer with facemask or mouthpiece in children with asthma.

BACKGROUND: Research 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. METHODS: Twelve 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. RESULTS: Mean (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). CONCLUSIONS: Lung 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.

Methodology for the in vitro evaluation of the delivery efficiency from valved holding chambers with facemasks.

BACKGROUND: In vitro performance studies of valved holding chamber (VHC)-facemask systems are a cost-effective means of circumventing potentially confounding clinical variables. This article reports results of an in vitro investigation into VHC-facemask performance, using three age-specific soft anatomical model (SAM) faces, under clinically relevant conditions. METHODS: A potentially standardized method was developed to assess VHC-facemask seal leakage, and evaluate the in vitro delivery efficiency of conventional and antistatic VHC-facemask systems. A custom-built test rig and VHC cradles were used to position the VHC-facemask systems against the SAM faces, with a constant, reproducible force. A standardized simulated pediatric breathing pattern (tidal volume = 155 mL; inhalation:exhalation ratio = 40:60; 25 breaths/min) was utilized. Percent facemask seal leakage, percent delivered dose, and the effect of different numbers of simulated breaths (2 to 8) were investigated. RESULTS: Of the VHC-facemask systems tested, the OptiChamber Diamond VHC with LiteTouch facemask (Diamond) system had the lowest percent seal leakage with each SAM face. Percent seal leakage from the other VHC-facemask systems was similar with SAM0 and SAM2 faces; the AeroChamber Plus Z-Stat VHC with ComfortSeal facemask (AC Z-Stat) system had a substantially greater percent seal leakage with the SAM1 face. Regardless of the number of simulated breaths, the Diamond system delivered the greatest mean percent delivered dose, with the lowest coefficient of variation, with each SAM face. Percent delivered dose did not correlate well with seal leakage, particularly for VHC-facemask systems with high seal leakage. The electrostatic properties of the VHCs appeared to influence drug delivery. CONCLUSIONS: This study describes a potentially standardized method for the evaluation of VHC-facemask systems. Use of this method enabled a comprehensive investigation into the influence of clinically relevant variables, including age-specific facial anatomy, number of simulated breaths, and seal leakage, on the delivery efficiency of several commercially available VHC-facemask systems.

Challenges and opportunities in respiratory drug delivery devices.

Recent reviews conclude that there is a need to improve the management of respiratory diseases treated with inhaled drugs, mainly asthma and chronic obstructive pulmonary disease (COPD). Healthcare professionals - mainly in primary care - seem to lack to some degree the evidence-based information required for the selection of the most appropriate respiratory drug delivery devices (inhalers) for the patients, whereas some of the patients often tend to have poor inhaler technique. This could have an impact on the ability to control the respiratory diseases in question. There are probably several reasons for these apparent challenges in the primary care arena. Owing to the abundance of inhalers available at present, especially for the treatment of asthma and COPD, it is quite a challenge to pick the 'right' inhaler for each patient. For an inhaler to be optimal, the patient has to be able to master the inhaler technique required for the specific inhaler. The patient-inhaler interfaces - mouthpieces or facemasks - can add important challenges that further diminish the efficacy of the treatment.

Bone mineral density in children treated with daily or periodical inhaled budesonide: the Helsinki Early Intervention Childhood Asthma study.

In a double-blind, randomized study, 136 children, 5-10-y-old, with newly detected persistent asthma received budesonide (BUD) 400 microg twice daily for 1 mo and thereafter 200 microg twice daily for 5 mo. Thereafter, 50 children were treated with BUD 100 microg twice daily, whereas 44 children used BUD as needed for 1 y; an additional 42 children received disodium cromoglycate (DSCG). Asthma exacerbations were treated with BUD for 2 wk in a dose of 400 microg twice daily in all groups. In this secondary analysis, bone mineral density (BMD) of the lumbar vertebrae was measured before and after the 18-mo treatment. Compared with DSCG, regular BUD treatment resulted in a significantly smaller increase in BMD (0.023 versus 0.034 g/cm; p = 0.023) and height (7.75 versus 8.80 cm; p = 0.001). Periodic treatment did not affect BMD. No intergroup differences were observed when BMD data were adjusted for changes in height. Daily BUD treatment in prepubertal children may slow down the increment in BMD and standing height. This was not observed in children receiving BUD periodically after the initial regular BUD treatment. The correlation between height and BMD suggests that following children's height might afford an estimation of inhaled corticosteroid effects on bone.

The Adaptive Aerosol Delivery system in a telehealth setting: patient acceptance, performance and feasibility.

BACKGROUND: The telehealth service is one of the fastest growing healthcare segments. It is increasingly utilizing computer technology and telecommunication equipment to either provide continuous vital sign monitoring or facilitate patient care at home, rather than relying solely on in-person care. METHODS: We conducted a 6-week open study in nineteen patients with cystic fibrosis enrolled from three centers, to investigate patient perception of a telehealth enabled nebulizer system (Prodose Adaptive Aerosol Delivery [AAD] System), which enabled the doorstep delivery of repeat medication. RESULTS: The results showed that patient confidence in the device and perception of ease of use was high with no significant change between the start and end of the trial. Views on the home delivery of medication were split between 'great' and 'inconvenient.' However, if the delivery system had been more flexible and delivered all the patients' drugs, the majority of patients would have had their medication delivered in this way. CONCLUSIONS: The trial showed that it was possible to build telehealth technology into an advanced nebulizer system, and that patient acceptance of the technology was unlikely to be a barrier to the adoption of such a telehealth system.

Mode of breathing-tidal or slow and deep-through the I-neb Adaptive Aerosol Delivery (AAD) system affects lung deposition of (99m)Tc-DTPA.

BACKGROUND: The I-neb AAD System was designed to deliver aerosol with two different breathing pattern algorithms: the Tidal Breathing Mode (TBM) and the Target Inhalation Mode (TIM). For the purpose of the study, the TBM breathing pattern algorithm was set to guide the subjects to inhalation during tidal breathing with aerosol pulsed during 50-80% of the time spent on inhalation, whereas the TIM breathing pattern was set to guide the subject to a slow and deep inhalation of up to approximately 9 sec with aerosol pulsed for up to 7 sec, leaving 2 sec for particle deposition in the lungs. In TIM, the inspiratory flow was guided to approximately 20 L/min through a built-in resistance in the mouthpiece. METHODS: We have, in a randomized, open-label, crossover study of 12 healthy subjects evaluated lung deposition following administration of a radiolabeled aerosol from the I-neb AAD System with the TBM and TIM breathing patterns. RESULTS: The results showed that mean lung deposition was significantly higher when using the I-neb AAD System with the TIM breathing pattern (73.3%) than with the TBM breathing pattern (62.8%). The mean exhaled fractions were low (<1%) for both breathing patterns. The nebulization time was significantly shorter with the TIM breathing pattern (3.0 min) than with the TBM breathing pattern (4.7 min). CONCLUSIONS: The results of the present study showed that lung deposition with the slow and deep inhalation achieved through the I-neb AAD System in TIM was superior to the lung deposition achieved during tidal breathing in TBM. With the combination of high lung deposition, almost no loss of aerosol during exhalation, and short nebulization time the I-neb AAD System with the TIM breathing pattern should be of special value to patients who require multiple daily dosing of aerosolized medication, are using drugs that should not be wasted into the room air, or would benefit from a more efficient delivery system.

Domiciliary experience of the Target Inhalation Mode (TIM) breathing maneuver in patients with cystic fibrosis.

BACKGROUND: The time requirements for multiple daily nebulizer treatments are important impediments to the quality of life for most patients with cystic fibrosis (CF). The I-neb Adaptive Aerosol Delivery (AAD) System can be used with a new mode of breathing during inhalation of aerosol, the Target Inhalation Mode (TIM). As a function of the TIM algorithm, the patient is guided to a slow and deep inhalation, which can result in shorter treatment times. METHODS: This study was conducted as a 3-month patient handling study of the I-neb AAD System in 42 patients with CF aged 12-57 years. The I-neb AAD System was supplied in both the standard Tidal Breathing Mode (TBM), and in TIM. Patients were trained to use the I-neb AAD System in TIM for the delivery of all their inhaled medications, but if they were not comfortable with the TIM maneuver they could change to the TBM maneuver. The primary variables were compliance with the correct use of the I-neb AAD System, and treatment times. The secondary variables were based on study questionnaires at the end of the study and covered ease of use, patient confidence, and patient satisfaction with the I-neb AAD System. RESULTS: There were a total of 10,240 complete treatments and of these, 8979 (88%) were in TIM. Compliance with the correct use of the I-neb AAD System was 97.6%. The mean treatment time for complete treatments in TIM was 4.20 min, compared with 6.83 min when using the I-neb AAD System in TBM. The responses to the questionnaires indicated that over 77% of the patients found the I-neb AAD System in TIM to be either: very easy, easy, or acceptable to use. CONCLUSIONS: The results demonstrated that by using the I-neb AAD System in TIM, a 40-50% reduction of nebulizer treatment times, and a high level of compliance could be achieved. The results also showed that the patients found the I-neb AAD System easy to use.

Evaluation of patient-reported outcomes and quality of life with the I-neb AAD system in patients with chronic obstructive pulmonary disease.

BACKGROUND: The I-neb Adaptive Aerosol Delivery (AAD) System is a novel portable mesh nebulizer that provides patient feedback regarding adherence to prescribed treatment and compliance with the correct use of the device. METHODS: This multicenter study was composed of 98 patients aged 53-80 years with Chronic Obstructive Pulmonary Disease (COPD). The primary variables were ease of use and satisfaction, which were assessed after 3 months of use of the I-neb AAD System (assessed at visit 2) and after 3 months of use of the patient's previous nebulizer system (assessed at visit 1) using matched questions from pre- and poststudy questionnaires. Quality of life was also assessed at visits 1 and 2 using the validated Chronic Respiratory Questionnaire (CRQ), which consists of dyspnea, emotional function, fatigue, and mastery domains. Differences in the distribution of responses between the pre- and poststudy ease of use and satisfaction questions were analyzed using the Marginal Homogeneity test. Differences in mean CRQ scores between the pre- and poststudy assessments were analyzed using the Wilcoxon Signed-Rank test. RESULTS: Patient responses on the ease of use and satisfaction questions significantly (p < or = 0.001) favored the I-neb AAD System compared with the patient's previous nebulizer system. In addition, significant (p < or = 0.015) improvements in the CRQ dimensions of dyspnea and fatigue were reported with the I-neb AAD System compared with the patients' previous nebulizer systems. CONCLUSIONS: The results from this study demonstrated that patients were more satisfied with the I-neb AAD System and found it easier to use than their previous nebulizer systems. In addition, the I-neb AAD System significantly improved dyspnea and fatigue compared with the patients' previous nebulizer systems, which may reflect improved adherence or more correct use of the nebulizer system with the I-neb AAD System.

Skin thickness in children treated with daily or periodical inhaled budesonide for mild persistent asthma. The Helsinki early intervention childhood asthma study.

In adults, asthma treatment with high doses of inhaled corticosteroids has resulted in dermal thinning. The aim of this study was to investigate the skin thickness in children with asthma during budesonide treatment. In a double-blind study, 113 children, 5-10 y old, with persistent asthma received budesonide 400 microg twice daily for 1 mo and thereafter 200 microg twice daily for 5 mo. Thereafter, 56 children received 100 microg twice daily for 1 y, whereas 57 other children used budesonide periodically for exacerbations. An additional 54 children were treated with disodium cromoglycate (DSCG) for 18 mo. Skin thickness was measured on each forearm before and after treatment for 6, 12, and 18 mo using a 20-MHz high-resolution ultrasonic device. The initial 6-mo budesonide treatment resulted in a greater reduction in mean skin thickness in the forearms compared with DSCG (right: -35.9 versus -5.9 microm; p = 0.004; left: -30.6 versus -7.3 microm; p = 0.03). At month 18, the inter-group differences were no longer significant. Budesonide inhalations in daily doses of 400-800 microg in prepubertal children with newly detected asthma may cause minor dermal thinning. The changes were reversible during low dose or periodic treatment with budesonide.

Thirteen-year follow-up of early intervention with an inhaled corticosteroid in patients with asthma.

BACKGROUND: In a 3-year study, adult patients who recently developed asthma (symptoms for less than 1 year) were treated for 2 years with the inhaled corticosteroid (ICS) budesonide (early therapy) or terbutaline. During the third year of the study, terbutaline-treated patients received budesonide (delayed therapy). Differences in lung function and bronchial responsiveness to histamine were observed between the 2 groups. OBJECTIVE: We compared the effects of early versus delayed budesonide therapy after a 10-year follow-up period (13 years after the study began) and current real-life data. METHODS: Of the original 103 patients, 90 were re-examined 13 years after study initiation. After the third year of the study, all patients had their medications, including the dose of ICS, individually adjusted. RESULTS: After the follow-up period, lung function was within the normal range for the entire group (all patients); bronchial responsiveness significantly improved compared with baseline data. No statistically significant differences in clinical or functional variables were found between patients given early or delayed budesonide therapy. However, the delayed therapy group had a higher neutrophil count and higher concentrations of eosinophilic cationic protein and myeloperoxidase in induced sputum. This group had also used more asthma medication and hospital days. CONCLUSIONS: Patients with relatively mild asthma who received ICS within 12 months of their first asthma symptoms or after a 2-year delay achieved equally good functional control of asthma after 10 years of individualized therapy. However, the delayed therapy group exhibited slightly less optimal disease control and more signs of airway inflammation.

Jet nebulizers versus pressurized metered dose inhalers with valved holding chambers: effects of the facemask on aerosol delivery.

The delivery of an aerosolized drug to a child is a complex process requiring an interaction between parent, child, and inhalation device. Recent studies have shown that the facemask can be a key factor affecting aerosol delivery, particularly the influence of leaks between the facemask and the face. To further quantify these effects and design around them, we have developed a bench model consisting of a breathing simulator, an inhaled mass filter, and a "pediatric face." This paper reviews the development of this model and details important decisions made in its configuration, particularly inhaled mass filter location (e.g., between device and facemask, or in mouth) and mouth diameter (4 or 18 mm). With the final design, we used the model to measure the impact of the "blow-by" technique on nebulizer inhaled mass. In a separate series of experiments, we studied the effects of a "crying" pediatric breathing pattern on inhaled mass for both nebulizers and pressurized metered dose inhalers with valved holding chambers (pMDI VHCs). Results indicated that the location of the inhaled mass filter was a critical factor in assessing aerosol delivery through facemasks and that the "mouth diameter" was not an important variable. Failure to locate the filter in the mouth behind the face, especially for jet nebulizers, failed to accurately measure effects of the facemask and significantly overestimated aerosol delivery. Blow-by results indicated that a 1-cm gap between the facemask and the face was not critical when using a front-loaded facemask. Finally, even with optimal design, the combination of an aerosol generator and facemask with a crying breathing pattern reduced the inhaled mass to 1% of the label dose.

Delivery of iloprost inhalation solution with the HaloLite, Prodose, and I-neb Adaptive Aerosol Delivery systems: an in vitro study.

BACKGROUND: Iloprost (Ventavis) inhalation solution is approved in doses of 2.5 microg and 5.0 microg for treatment of pulmonary arterial hypertension (World Health Organization group I) in patients with New York Heart Association class III or IV symptoms, delivered with 2 Adaptive Aerosol Delivery (AAD) systems: Prodose and I-neb. The HaloLite device was the first-generation AAD system used in the clinical delivery of inhaled iloprost, and I-neb is the third-generation system. OBJECTIVE: Study the in vitro performance of the HaloLite, Prodose, I-neb, in terms of mass median aerodynamic diameter (MMAD), fine-particle fraction (FPF, percent of aerosol droplets < 4.7 microm), and inhaled mass of iloprost. METHODS: To analyze the MMAD and FPF, we collected the aerosol from each device with a cascade impactor. Because the devices are breath-actuated, airflow was regulated with flow-control valves to create inhalation and exhalation. To measure the inhaled mass of iloprost we used a breathing simulator with a filter system between the simulator and the device, and quantified the captured aerosol with iloprost-specific chromatography. RESULTS: With the HaloLite, Prodose, and I-neb, respectively: the MMADs were 1.4 microm, 1.7 microm, and 2.1 microm; the FPFs were 91%, 82%, and 82%. The inhaled mass with the 2.5-microg dose ranged from 2.8 microg to 2.9 microg. The inhaled mass with the 5.0-microg dose ranged from 4.8 microg to 5.2 microg. CONCLUSION: The HaloLite, Prodose, and I-neb AAD systems have comparable MMADs, FPFs, and inhaled mass with iloprost.

Variation in pediatric aerosol delivery: importance of facemask.

We have quantified in vitro the influence of the facemask on the amount of drug delivered (e.g., inhaled mass) by jet nebulizer and pressurized metered dose inhaler (pMDI) valved holding chamber (VHC) combinations (non-detergent-coated and detergent-coated). Pediatric breathing patterns were used with a breathing simulator, which was connected to a face onto which each device was positioned. An inhaled mass filter interposed between the simulator and the face captured the aerosolized drug. Budesonide inhalation suspension (0.25 mg) was used with the jet nebulizers and fluticasone propionate (220 microg) pMDI with the VHCs. Maximal drug delivery was measured using constant flow through each device. Breathing pattern effects were assessed for sealed devices (no leaks) and with facemasks (possible leaks at the facemask). Inhaled mass from both nebulizers and pMDI VHCs was affected by breathing pattern, but compared to nebulizers the pMDI VHCs were significantly more variable and sensitive to several factors. The influence of VHC conditioning combined with effects of breathing pattern resulted in the inhaled mass ranging from 0.7 +/- 0.5 to 53.3 +/- 6.2%. Nebulizers were less variable (9.6 +/- 0.7 to 24.3 +/- 3.1%). Detergent coating of VHC markedly increased the inhaled mass and reproducibility of drug delivery (27.2 +/- 1.4 to 53.3 +/- 6.2%) for pMDI VHC combinations, but these effects were lost in the presence of facemasks. Using pediatric patterns of breathing, nebulizer/facemask combinations delivered 4.1 +/- 0.8 to 19.3 +/- 2.3% of the label dose while pMDI and detergent-coated VHC delivered 4.0 +/- 1.6 to 28.6 +/- 2.5%. Facemask seal is a key factor in drug delivery. Leaks around the facemask reduce drug delivery and for pMDI VHCs can negate effects of detergent coating.