Development and Evaluation of a Family of Human Face and Upper Airway Models for the Laboratory Testing of Orally Inhaled Products.

Many orally inhaled products are supplied with a facemask instead of a mouthpiece, enabling aerosolized medication to be transferred from the inhaler to the lungs when the user lacks the capability to use a mouthpiece. Until recently, laboratory evaluation of an orally inhaled product-facemask was frequently undertaken by removing the facemask, treating the facemask adapter as being equivalent to a mouthpiece. Measurements of delivered drug mass were therefore subject to bias arising from the absence of dead volume, had the facemask been present. We have described the development of the Aerosol Delivery to an Anatomic Model (ADAM) infant, small child, and adult faces and upper airways, and their subsequent evaluation. Each model possesses physical features of appropriate size, and the soft tissues are also simulated. Rudimentary underlying bony structure is also present, because its purpose is only to provide support, enabling the mechanical response of the facial soft tissues when a facemask is applied to be realized. A realistic upper airway (nasopharynx for the infant model, naso- and oropharynx for the child and oropharynx for the adult models) is also incorporated, so that each model can be used to determine the mass of inhaled medication likely to penetrate as far as the lungs where therapy is intended to be applied. Measurements of the mass of pressurized metered-dose inhaler-delivered salbutamol at a filter distal to the upper airway of each model, simulating age-appropriate tidal breathing, were remarkably consistent, almost all being in the range 0.3 to 1.0 µg/kg across the model age ranges, when expressed as a fraction of body weight.

Are the Reference Values for the Provocative Concentration of Methacholine Appropriate for Children?

Background: Preliminary data in a randomly selected pediatric cohort study in 8-year-olds suggested a rate of positivity to a methacholine challenge test that was unexpectedly high, roughly 30%. The current recommendation for a negative methacholine test is a 20% decrease in the forced expiratory volume in one second at a dose greater than 400 µg. This was derived from studies in adults using the obsolete English Wright nebulizer. One explanation for the high incidence of positivity in the study in 8-year-olds could be that children deposit more methacholine on a µg/kg basis than adults, due to differences in their breathing patterns. The purpose of this study was to determine if pediatric breathing patterns could result in a higher dose of methacholine depositing in the lungs of children based on µg/kg body weight compared with adults. Methods: An AeroEclipse Breath Actuated nebulizer delivered methacholine aerosol, generated from a 16 mg/mL solution, for one minute, using age-appropriate breathing patterns for a 70 kg adult and a 30 and 50 kg child produced by a breathing simulator. Predicted lung deposition was calculated from the collected dose of methacholine on a filter placed at the nebulizer outport, multiplied by the fraction of the aerosol mass contained in particles ≤5 µm. The dose of methacholine on the inspiratory filter was assayed by high performance liquid chromatography (HPLC). Particle size was measured using laser diffraction technology. Results: The mean (95% confidence intervals) predicted pulmonary dose of methacholine was 46.1 (45.4, 46.8), 48.6 (45.3, 51.9), and 36.1 (34.2, 37.9) µg/kg body weight for the 30 kg child, 50 kg child, and 70 kg adult, respectively. Conclusions: On a µg/kg body weight, the predicted pulmonary dose of methacholine was greater with the pediatric breathing patterns than with the adult pattern.

Interchanging Reusable and Disposable Nebulizers Used with Home-Based Compressors May Result in Inconsistent Dosing: A Laboratory Investigation with Device Combinations Supplied to the US Healthcare Environment.

INTRODUCTION: Reusable nebulizer-compressor combinations deliver inhaled medications for patients with chronic lung diseases. On hospital discharge, the patient may take home the disposable nebulizer that was packaged and combine it with their home compressor. Though this practice may reduce waste, it can increase variability in medication delivery. Our study compared several reusable and disposable nebulizers packaged with compressor kits used in the US. We included a common disposable hospital nebulizer that may not be supplied with popular home kits but may be brought home after a hospitalization or emergency department visit. We focused on fine droplet mass < 4.7 µm aerodynamic diameter (FDM<4.7 µm), associated with medication delivery to the airways of the lungs. METHODS: We evaluated the following nebulizer-compressor combinations (n = 5 replicates): 1. OMBRA® Table Top Compressor with MC 300® reusable and Airlife™ MistyMax™ 10® disposable nebulizer, 2. Sami-the-Seal® compressor with SideStream® reusable and disposable nebulizers and Airlife™ MistyMax 10™ disposable nebulizer, 3. VIOS® compressor with LC Sprint® reusable, and VixOne® and Airlife™ MistyMax™ disposable nebulizers, 4. Innospire® Elegance® compressor with SideStream® reusable and disposable nebulizers and Airlife™ MistyMax 10™ disposable nebulizer, 5. Willis-the-Whale® compressor with SideStream® reusable and disposable nebulizers and Airlife™ MistyMax 10™ disposable nebulizer, 6. Pari PRONEB® Max compressor with LC Sprint® reusable and Airlife™ MistyMax 10™ disposable nebulizer. We placed a 3-ml albuterol solution (0.833 mg/ml) in each nebulizer. A bacterial/viral filter was attached to the nebulizer mouthpiece to capture emitted medication, with the filter exit coupled to a simulator of a tidal breathing adult (rate = 10 cycles/min; Vt = 600 ml; I/E ratio = 1:2). The filter was replaced at 1-min intervals until onset of sputter. Droplet size distributions (n = 5 replicates/system) were determined in parallel by laser diffractometry. RESULTS: Cumulative FDM<4.7 µm varied from 381 ± 33 µg for the best performing combination (Proneb/LC-Sprint) to 150 ± 21 µg for the system with the lowest output (VIOS®/MistyMax 10™). CONCLUSIONS: Substituting one nebulizer for another can result in large differences in medication delivery to the lungs.

A novel, versatile valved holding chamber for delivering inhaled medications to neonates and small children: laboratory simulation of delivery options.

BACKGROUND: Delivery of bronchodilator to infants and small children from a pressurized metered-dose inhaler with valved holding chamber (pMDI-VHC) is limited by airway narrowness, short respiratory cycle time, and small tidal volume (V(T)). There is a need for a versatile, efficient VHC, given the variety of treatment modalities. METHODS: We tested the AeroChamber Mini VHC (the internal geometry of which is optimized for aerosol delivery, and which accepts a pMDI canister that has a dose counter) in experiments to determine differences in the delivery of hydrofluoroalkane-propelled albuterol (90 microg/actuation) during: mechanical ventilation via endotracheal tube (ETT); manual resuscitation via ETT; and spontaneous breathing via face mask. We tested 5 units of the AeroChamber Mini VHC per test. We simulated the tidal breathing of a premature neonate (V(T) 6 mL), a term neonate (V(T) 20 mL), and a child approximately 2 years old (V(T) 60 mL). We collected the aerosol on an electret filter and quantitatively assayed for albuterol. RESULTS: The total emitted mass of albuterol per actuation that exited the VHC was marginally greater during spontaneous breathing (12.1 +/- 1.8 microg) than during manual resuscitation (10.0 +/- 1.1 microg) (P = .046). Albuterol delivery via mechanical ventilation, though comparable with the premature-neonate model (3.3 +/- 1.2 microg), the term-neonate model (3.8 +/- 2.1 microg), and the 2-y-old-child model (4.2 +/- 2.3 microg) (P = .63), was significantly lower than in the spontaneous-breathing and manual-resuscitation models (P < .001). In the neonatal models the total emitted mass was similar with the spontaneous-breathing model (6.0 +/- 1.0 microg with the premature-neonate model, 10.5 +/- 0.7 microg with the term-neonate model) and the manual-resuscitation model (5.5 +/- 0.3 microg premature-neonate model, 10.7 +/- 0.9 microg term-neonate model) (P > or = .46 via one-way analysis of variance). CONCLUSION: The reduced delivery of albuterol during mechanical ventilation (compared to during spontaneous breathing and manual resuscitation via ETT) was probably associated with the saturated atmosphere in the breathing circuit (37 degrees C, relative humidity > 99%), compared to the ambient air (22 +/- 1 degrees C, 44 +/- 7% relative humidity). The AeroChamber Mini VHC may provide a versatile alternative to VHCs that are designed exclusively for one aerosol treatment modality.

Relative precision of inhaler aerodynamic particle size distribution (APSD) metrics by full resolution and abbreviated andersen cascade impactors (ACIs): part 1.

The purpose of this study was to compare relative precision of two different abbreviated impactor measurement (AIM) systems and a traditional multi-stage cascade impactor (CI). The experimental design was chosen to provide separate estimates of variability for each impactor type. Full-resolution CIs are useful for characterizing the aerosol aerodynamic particle size distribution of orally inhaled products during development but are too cumbersome, time-consuming, and resource-intensive for other applications, such as routine quality control (QC). This article presents a proof-of-concept experiment, where two AIM systems configured to provide metrics pertinent to QC (QC-system) and human respiratory tract (HRT-system) were evaluated using a hydrofluoroalkane-albuterol pressurized metered dose inhaler. The Andersen eight-stage CI (ACI) served as the benchmark apparatus. The statistical design allowed estimation of precision with each CI configuration. Apart from one source of systematic error affecting extra-fine particle fraction from the HRT-system, no other bias was detected with either abbreviated system. The observed bias was shown to be caused by particle bounce following the displacement of surfactant by the shear force of the airflow diverging above the collection plate of the second impaction stage. A procedure was subsequently developed that eliminated this source of error, as described in the second article of this series (submitted to AAPS PharmSciTech). Measurements obtained with both abbreviated impactors were very similar in precision to the ACI for all measures of in vitro performance evaluated. Such abbreviated impactors can therefore be substituted for the ACI in certain situations, such as inhaler QC or add-on device testing.

Relative precision of inhaler aerodynamic particle size distribution (APSD) metrics by full resolution and abbreviated andersen cascade impactors (ACIs): part 2--investigation of bias in extra-fine mass fraction with AIM-HRT impactor.

The purpose of this study was to resolve an anomalously high measure of extra-fine particle fraction (EPF) determined by the abbreviated cascade impactor possibly relevant for human respiratory tract (AIM-HRT) in the experiment described in Part 1 of this two-part series, in which the relative precision of abbreviated impactors was evaluated in comparison with a full resolution Andersen eight-stage cascade impactor (ACI). Evidence that the surface coating used to mitigate particle bounce was laterally displaced by the flow emerging from the jets of the lower stage was apparent upon microscopic examination of the associated collection plate of the AIM-HRT impactor whose cut point size defines EPF. A filter soaked in surfactant was floated on top of this collection plate, and further measurements were made using the same pressurized metered-dose inhaler-based formulation and following the same procedure as in Part 1. Measures of EPF, fine particle, and coarse particle fractions were comparable with those obtained with the ACI, indicating that the cause of the bias had been identified and removed. When working with abbreviated impactors, this precaution is advised whenever there is evidence that surface coating displacement has occurred, a task that can be readily accomplished by microscopic inspection of all collection plates after allowing the impactor to sample ambient air for a few minutes.

Electrostatics and inhaled medications: influence on delivery via pressurized metered-dose inhalers and add-on devices.

The movement of inhaler-generated aerosols is significantly influenced by electrostatic charge on the particles and on adjacent surfaces. Particle charging arises in the aerosol formation process. Since almost all inhalers contain nonconducting components, these surfaces can also acquire charge during manufacture and use. Spacers and valved holding chambers used with pressurized metered-dose inhalers to treat obstructive lung diseases are particularly prone to this behavior, which increases variability in the amount of medication available for inhalation, and this is exacerbated by low ambient humidity. This may result in inconsistent medication delivery. Conditioning the device by washing it with a conductive surfactant (detergent) or using devices made of charge-dissipative/conducting materials can mitigate electrostatic charge. This review discusses sources of electrostatic charge, the processes that influence aerosol behavior, methods to mitigate electrostatic charge, and potential clinical implications.

Levalbuterol aerosol delivery with a nonelectrostatic versus a nonconducting valved holding chamber.

BACKGROUND: Hydrofluoroalkane-propelled levalbuterol (Xopenex) aerosol is a recently approved formulation for delivery via metered-dose inhaler for the treatment or prevention of bronchospasm in adults, adolescents, and children > or = 4 years of age who have reversible obstructive airway disease. Valved holding chambers (VHCs) made from conventional polymers are susceptible to accumulation of electrostatic charge, which can be minimized by prewashing with ionic detergent, but it may be desirable to be able to use the product straight from the package, without pretreatment, especially during an exacerbation. METHODS: We studied the performance of the AeroChamber Plus and AeroChamber Max VHCs in delivering hydrofluoroalkane-propelled levalbuterol. Both VHCs were prewashed, rinsed, and drip-dried before testing. The AeroChamber Max is manufactured from charge-dissipative material and was therefore also evaluated without prewashing. Aerosol samples were collected at 28.3 L/min with an Andersen 8-stage cascade impactor, per the procedure specified in Chapter 601 of the United States Pharmacopeia. RESULTS: The mean +/- SD fine-particle mass (mass of aerosol particles < 4.7 microm aerodynamic diameter) values were 33.5 +/- 1.4 microg and 36.3 +/- 1.1 microg with the AeroChamber Max, without and with wash/rinse pretreatment, respectively, and 28.5 +/- 2.4 microg with the prewashed AeroChamber Plus. CONCLUSIONS: We think the small differences we observed are unlikely to be of clinical importance, given the inter-patient variability seen with inhaled drug delivery. The performance of the AeroChamber Max was substantially comparable whether or not it was prewashed.

The importance of nonelectrostatic materials in holding chambers for delivery of hydrofluoroalkane albuterol.

INTRODUCTION: Electrostatic attraction of aerosolized particles to the inner walls of an aerosol holding chamber (HC) made from a nonconducting material can reduce medication delivery, particularly if there is a delay between actuation and inhalation. OBJECTIVE: Compare total emitted mass and fine-particle mass (mass of particles < 4.7 microm) of hydrofluoroalkane-propelled albuterol from similar-sized HCs manufactured from conductive material (Vortex), charge-dissipative material (AeroChamber Max), and nonconductive material (OptiChamber Advantage, ProChamber, Breathrite, PocketChamber, and ACE), with and without wash/rinse pretreatment of the HC interior with ionic detergent, and with 2-s and 5-s delays between actuation and inhalation. METHODS: All the HCs were evaluated (1) directly from their packaging (with no wash/rinse pretreatment) and (2) after washing with ionic detergent and rinsing and drip-drying. We used an apparatus that interfaced between the HC mouthpiece and the induction port of an 8-stage Andersen cascade impactor to simulate a poorly coordinated patient, with delays of 2 s and 5 s between actuation and inhalation/sampling, at 28.3 L/min. RESULTS: With the 2-s delay, the delivered fine-particle mass per actuation, before and after (respectively) wash/rinse pretreatment was: AeroChamber Max: 23.8 +/- 4.8 microg, 21.5 +/- 3.2 microg; Vortex: 16.2 +/- 1.7 microg, 15.5 +/- 2.0 microg; OptiChamber Advantage: 2.6 +/- 1.2 microg, 6.7 +/- 2.3 microg; ProChamber: 1.6 +/- 0.4 microg, 5.1 +/- 2.5 microg; Breathrite: 2.0 +/- 0.9 microg, 3.2 +/- 1.8 microg; PocketChamber: 3.4 +/- 1.6 microg, 1.7 +/- 1.6 microg; ACE: 4.5 +/- 0.9 microg, 5.4 +/- 2.9 microg. Similar trends, but greater reduction in aerosol delivery, were observed with the 5-s delay. Significantly greater fine-particle mass was delivered from HCs made from conducting or charge-dissipative materials than from those made from nonconductive polymers, even after wash/rinse pretreatment (p < 0.01). The fine-particle mass was also significantly greater from the AeroChamber Max than from the Vortex, irrespective of wash/rinse pretreatment or delay interval (p < 0.01). CONCLUSION: HCs made from electrically conductive materials emit significantly greater fine-particle mass, with either a 2-s or 5-s delay, than do HCs made from nonconducting materials, even with wash/rinse pretreatment.

Laser diffractometry as a technique for the rapid assessment of aerosol particle size from inhalers.

The rapid assessment of aerosols produced by medicinal inhalers is highly desirable from several standpoints, including the assurance of product quality, the development of new delivery systems, and the need to meet an increasing requirement by regulatory bodies for reliable in vitro performance data. Particle size analysis has traditionally been undertaken by cascade impactor on account of the direct assessment of active pharmaceutical ingredient(s) (APIs) that is possible by this method. However, laser diffractometry is less labor-intensive, more rapid, and can be a less invasive procedure. The technique provides meaningful results; as long as precautions are taken to validate that the measurements are an accurate reflection of the distribution of API mass as a function of particle or droplet size. We begin the review by examining the underlying theory of the laser diffraction method. After a brief description of current laser diffractometers used in inhaler measurements, we continue by examining the range of applications by inhaler class. We then examine the basis upon which inhaler measurements made by laser-diffractometry can be compared with equivalent particle size distribution data from compendial techniques. We conclude the assessment of the technique by developing guidelines for its valid application as a component of the range of in vitro methods that are available for inhaler performance assessment.

Comparison of three valved holding chambers for the delivery of fluticasone propionate-HFA to an infant face model.

The purpose of this study was to compare three valved holding chambers (VHC) with facemasks attached. One VHC (AeroChamber Max[TM] with medium mask) was made with materials that dissipate surface electrostatic charge, and the others (OptiChamber Advantage and ProChamber[TM] with pediatric facemask) were made from non-conducting materials. The OptiChamber Advantage and ProChamber VHCs were each washed with an ionic detergent and drip dried before testing to minimize surface electrostatic charge. The AeroChamber Max VHCs were tested "out of the package" and also after wash, rinse, and drying. An infant face model incorporating an electrostatic filter in the oral cavity was connected to a breath simulator using a standard waveform for a small child. The fit of each VHC with facemask was demonstrated by agreement of inspiratory flow measurements between a pneumotachograph connected to the system with those set on the simulator. An HFA-fluticasone propionate metered dose inhaler (MDI; 125 microg/dose) was inserted into the VHC, two actuations were delivered, and the filters were subsequently assayed using high-pressure liquid chromatography (HPLC). Testing and sample assay order was randomized, and HPLC assays were undertaken blinded. Drug delivery efficiency expressed as a percentage of the total dose of fluticasone propionate (250 microg) for the AeroChamber Max VHC "out-of-the-package" was 22.0(0.7)% (mean [99% CI]) and 21.2(1.5)% when pre-washed/rinsed. Results for the pre-washed ProChamber and OptiChamber Advantage VHCs were 10.2(0.55)% and 8.8(1.9)%, respectively. The more efficient delivery of medication via VHCs made from electrostatic charge dissipative materials should be considered when choosing doses for small children.

An in vitro study to investigate the use of a breath-actuated, small-volume, pneumatic nebulizer for the delivery of methacholine chloride bronchoprovocation agent.

BACKGROUND: Current American Thoracic Society and American Association for Respiratory Care guidelines for the delivery of aerosol agents such as methacholine chloride (MC) for bronchoprovocation testing require the use of pneumatic jet nebulizers that have well-defined droplet size and mass output. A recently developed disposable, breath-actuated nebulizer (AeroEclipse) may offer bronchoprovocation testers an alternative to existing devices. METHODS: We studied the performance of 5 AeroEclipse nebulizers with regard to mass of MC delivered with various MC solution concentrations and numbers of inhalations, using a model of adult tidal breathing. Each nebulizer was operated with compressed air (8 L/min at 50 psig) and an initial fill of 2 mL. MC solutions with mass concentrations of 0.25, 0.98, 3.85, and 15.70 mg/mL were tested. The total mass of MC delivered was determined after 5, 10, and 15 complete breathing cycles, by assaying the MC collected on a filter placed at the nebulizer mouthpiece. The aerosol droplet size distribution, fine droplet fraction (FDF) (percentage of droplets < 4.8 microm diameter), and fine droplet mass (FDM) (mass of droplets < 4.8 microm diameter) were determined by laser diffractometry, using physiologically normal saline as a surrogate for MC solution. RESULTS: The mean +/- SD FDM collected in 5 breathing cycles was 654 +/- 29 microg with the 15.70 mg/mL solution, 158 +/- 9 microg with the 3.85 mg/mL solution, 37 +/- 3 microg with the 0.98 mg/mL solution, and 7 +/- 2 microg with the 0.25 mg/mL solution. FDM showed a linear correlation (r(2) = 0.9999) with MC concentration, within the range studied. FDM also showed a linear correlation (r(2) = 0.999) with the number of breathing cycles. For instance, with the 15.70 mg/mL solution, FDM was 654 +/- 29 microg with 5 breathing cycles, 1,228 +/- 92 microg with 10 breathing cycles, and 1,876 +/- 132 microg with 15 breathing cycles. CONCLUSIONS: Although the bronchoprovocation test procedure had to be slightly modified from the guidelines to accommodate the operation of the AeroEclipse's breath-actuation feature, our measurements indicate that a predictable dose of MC, within the useful range for bronchoprovocation testing, can be delivered to an adult patient breathing tidally. The green indicator on the AeroEclipse could be used to coach the patient to inhale for a specific period, thereby controlling MC delivery per breathing cycle.

The delivery of chlorofluorocarbon-propelled versus hydrofluoroalkane-propelled beclomethasone dipropionate aerosol to the mechanically ventilated patient: a laboratory study.

UNLABELLED: We describe a laboratory investigation comparing the delivery of chlorofluorocarbon (CFC)- and hydrofluoroalkane (HFA)-formulated beclomethasone dipropionate (BDP) by metered-dose inhaler and holding chamber (AeroChamber HC MV) in a simulation of a mechanically ventilated adult patient. METHODS: We equipped each HC MV (n = 5) with an 8.0 mm diameter endotracheal tube (ETT), locating the HC MV in the inspiratory limb of a breathing circuit linked to a mechanical ventilator set to simulate tidal breathing at tidal volume = 830 mL, respiratory rate = 15 breaths/min, inspiratory-expiratory ratio of 1:2.1, peak inspiratory pressure = 20 cm H(2)O. Temperature and humidity settings were 35+/-1 degrees C and 100% relative humidity (close to body conditions). We compared delivery of 5-actuations of CFC- and HFA-BDP (both 50 microg/actuation), measuring total emitted mass captured by a filter at the distal end of the ETT. In a separate study, we inserted the distal end of the ETT within the entry cone of a cascade impactor so that the aerosol particle size distribution could be determined with the circuit at similar environmental conditions as described previously. We made benchmark measurements with circuit temperature and humidity at room ambient conditions (21+/-1 degrees C and 54+/-5% RH respectively). RESULTS: Total emitted mass (5 measurements/device) was significantly greater for HFA-BDP (14.1+/-1.1 microg/actuation) compared with CFC-BDP (2.4+/-0.8 microg/actuation) (paired t test, p < 0.001). More HFA-BDP (2.7 +/- 0.2 microg/actuation) was lost from the delivery system during exhalation (0.9 +/- 0.4 microg/actuation for CFC-BDP) (p < 0.001). The mass median aerodynamic diameter (MMAD) increased from 1.2 microm (room ambient) to 2.8 microm (higher temperature and humidity conditions) for HFA-BDP. In contrast, MMAD for CFC-BDP remained close to 4.6 microm under either condition, but particles finer than about 4.0 microm increased in size when the circuit was saturated. CONCLUSIONS: Total emitted mass for HFA-BDP was increased by a factor of 5.8 compared with CFC-BDP, due largely to the finer particle size distribution of the HFA-based solution formulation. Additional water vapor required to operate the breathing circuit at close to body conditions resulted in fine particle growth with both formulations.

Cascade impactors for the size characterization of aerosols from medical inhalers: their uses and limitations.

Cascade impactors, including the multi-stage liquid impinger, are by far the most widely encountered means for the in vitro determination of the particle size distribution of aerosols from medical inhalers, both in product development, batch release and in applications with add-on devices. This is because they directly measure aerodynamic size, which is the most relevant parameter to describe particle transport within the respiratory tract. At the same time, it is possible to quantify the mass of active pharmaceutical ingredient in different size ranges independent of other non-physiologically active components of the formulation. We begin by providing an overview of the operating principles of impactors and then highlight the various configurations and adaptations that have been adopted to characterize the various classes of inhaler. We continue by examining the limitations of the cascade impaction method, in particular looking at potential sources of measurement bias and discussing both appropriate and inappropriate uses of impactor-generated data. We also present a synopsis of current developments, including the Next Generation Pharmaceutical Impactor, and automation of cascade impactors for routine inhaler performance measurements.

Performance of large- and small-volume valved holding chambers with a new combination long-term bronchodilator/anti-inflammatory formulation delivered by pressurized metered dose inhaler.

The treatment of both the bronchoconstriction and inflammatory aspects of asthma simultaneously by a single pressurized metered dose inhaler (pMDI) represents a significant advance in convenience to the patient. However, a valved holding chamber (VHC) may still be needed to reduce the coarse component of the dose that is likely to deposit in the oropharyngeal region, and a small sized device may offer significant advantages to the patient from the standpoint of compliance with therapy. VHCs representing small (adult AeroChamber Plus with mouthpiece, 149-mL) and large (Volumatic, 750-mL) devices have been compared in an in vitro evaluation with Seretide/Advair (hydro-fluoro alkane [HFA]-formulated fluticasone propionate [FP = 125 microg/dose] and salmeterol xinafoate [SX = 25 microg/dose]) by Andersen Mark-II eight-stage impactor operated at 28.3 L/min following compendial methodology. Fine particle fraction, based on the size range from 1.1 to 4.7 microm aerodynamic diameter, from either large or small VHCs with either component (69-79%) was similar [p > or = 0.08], and significantly greater than that from the pMDI alone (approximately 40%) [p < 0.001]. Fine particle dose emitted by the VHCs for SX (8.2 +/- 0.8 microg for the AeroChamber Plus and 7.7 +/- 0.5 microg for the Volumatic) were comparable, and also similar to the fine particle dose delivered by the pMDI when used without a VHC (7.6 +/- 0.6 microg). Fine particle doses for the FP component delivered by the two VHCs (46.4 +/- 3.4 microg for the AeroChamber Plus and 46.3 +/- 2.7 microg for the Volumatic) were equivalent, but were slightly greater than the corresponding fine particle dose from the pMDI alone (39.1 +/- 2.6 microg). However, this difference (approximately 20%) is close to the limit of resolution based on intermeasurement variability and is unlikely to have clinical significance, given the interpatient variability seen with inhaled drug therapy. It is therefore concluded that either of these VHCs has equivalent in vitro performance with this combination formulation in terms of the portion of the dose emitted from the pMDI that is likely to reach the receptors in the lungs.

Size analysis of a pressurized metered dose inhaler-delivered solution formulation by an Aerosizer-LD time-of-flight aerosol particle size spectrometer.

In a previous study, an Aerosizer-LD time-of-flight (TOF) aerosol spectrometer was shown to underestimate significantly the aerodynamic size of airborne particles produced following actuation of a suspension-based formulation delivered from a pressurized metered-dose inhaler (pMDI) via a nonelectrostatic valved holding chamber (VHC). It was postulated that the nonspecific nature of the particle detection system in terms of chemical composition was responsible for the inclusion of smaller non-drug-containing excipient particles in the measured size distribution data from this analyzer. This limitation may not apply to certain solution formulations in which the only particles remaining after the evaporation of propellant and volatile excipient (solubilizer) are composed of pure drug substance. Such a formulation (QVAR, HFA-formulated beclomethasone di-propionate [BDP]) has recently become available, and the present investigation was therefore designed to test this hypothesis. Aerosizer-LD measured mass-weighted size distribution data for QVAR had a mass median aerodynamic diameter (MMAD) close to 1.1 microm, very similar to published data for this parameter, based on measurement of the aerosol by cascade impactor followed by drug-specific assay. However, the Aerosizer-LD underestimated the spread of the size distribution significantly. The causes are believed to be a combination of two separate effects: (1) lack of sensitivity of the particle detection system to particles finer than about 0.7 microm aerodynamic diameter and (2) preferential removal of particles larger than the MMAD, either by evaporation of residual solvent (ethanol) or by inertial/gravitational deposition in the sampling arrangement upstream of the measurement zone.

Aerodynamic particle size analysis of aerosols from pressurized metered-dose inhalers: comparison of Andersen 8-stage cascade impactor, next generation pharmaceutical impactor, and model 3321 Aerodynamic Particle Sizer aerosol spectrometer.

The purpose of this research was to compare three different methods for the aerodynamic assessment of (1) chloroflurocarbon (CFC)--fluticasone propionate (Flovent), (2) CFC-sodium cromoglycate (Intal), and (3) hydrofluoroalkane (HFA)--beclomethasone dipropionate (Qvar) delivered by pressurized metered dose inhaler. Particle size distributions were compared determining mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD), and fine particle fraction <4.7 microm aerodynamic diameter (FPF(<4.7 microm)). Next Generation Pharmaceutical Impactor (NGI)-size distributions for Flovent comprised finer particles than determined by Andersen 8-stage impactor (ACI) (MMAD = 2.0 +/- 0.05 micro m [NGI]; 2.8 +/- 0.07 microm [ACI]); however, FPF(<4.7 microm) by both impactors was in the narrow range 88% to 93%. Size distribution agreement for Intal was better (MMAD = 4.3 +/- 0.19 microm (NGI), 4.2 +/- 0.13 microm (ACI), with FPF(<4.7 microm) ranging from 52% to 60%. The Aerodynamic Particle Sizer (APS) undersized aerosols produced with either formulation (MMAD = 1.8 +/- 0.07 micro m and 3.2 +/- 0.02 micro m for Flovent and Intal, respectively), but values of FPF(<4.7 microm)from the single-stage impactor (SSI) located at the inlet to the APS (82.9% +/- 2.1% [Flovent], 46.4% +/- 2.4% [Intal]) were fairly close to corresponding data from the multi-stage impactors. APS-measured size distributions for Qvar (MMAD = 1.0 +/- 0.03 micro m; FPF(<4.7 micro m)= 96.4% +/- 2.5%), were in fair agreement with both NGI (MMAD = 0.9 +/- 0.03 micro m; FPF(<4.7 microm)= 96.7% +/- 0.7%), and ACI (MMAD = 1.2 +/- 0.02 microm, FPF(<4.7 microm)= 98% +/- 0.5%), but FPF(<4.7 microm) from the SSI (67.1% +/- 4.1%) was lower than expected, based on equivalent data obtained by the other techniques. Particle bounce, incomplete evaporation of volatile constituents and the presence of surfactant particles are factors that may be responsible for discrepancies between the techniques.

Improved laboratory test methods for orally inhaled products.

Existing pharmacopeial methods for the in vitro testing of orally inhaled products (OIPs) are simplified representations of clinical reality, as their objective is to provide metrics that are discriminating of product quality. Attempts to correlate measures such as fine particle fraction <5 µm aerodynamic diameter with in vivo measures of lung deposition have therefore been notoriously difficult to achieve. Although particle imaging-based techniques may be helpful to link in vitro to in vivo data as surrogates for clinical responses, a reappraisal of the purposes for laboratory-based testing of OIPs is required. This article provides guidance on approaches that may be helpful to develop clinically appropriate methods to assess OIP performance in the laboratory, with the ultimate goal of developing robust in vitro-in vivo relationships for the major inhaled drug classes.

Oral inhalation therapy: meeting the challenge of developing more patient-appropriate devices.

Although oral inhalers have been mass produced for more than 50 years, there is a large body of literature in which evidence has been provided that patients either misuse their inhalers inadvertently or deliberately, thereby reducing their intended efficacy or, in the worst cases, rendering them altogether ineffective. In general, inhalers are becoming increasingly complicated with the incorporation of add-on devices, miniaturized electronics and ever more complex mechanical systems that aid aerosol delivery to the lower respiratory tract and, at the same time provide user feedback. However, these benefits often come at a significant cost, and there are signs that increasing attention will need to be given to the cost-benefit equation in the future. This review explores the development of pressurized metered-dose inhalers, dry powder inhalers and devices for liquid-droplet dispersal and inhalation from the perspective of the patient, by focusing on aspects that improve user interaction. These include designed-in features, such as breath-enhanced or breath-actuated operation that interact with the breathing pattern of the user, as well as more direct feedback aids that confirm, to the patient or healthcare provider that the dose has been delivered and that the patient has inhaled.