Journal of Aerosol Medicine and Pulmonary Drug Delivery

Metered-dose inhalers (MDI) are routinely used to administer inhaled antiasthma drugs. Actuation-inhalation coordination problems are overcome and systemic side effects are reduced by using spacers/holding chambers (SP/HCHs). Many of these devices do not allow the use of the manufacturer's actuator. The objectives of this study were (a) to investigate the effect of the interaction of eight MDI products with four different SP/HCHs on their metering performance (MP); and (b) to test the hypothesis whether the MP obtained with a SP/HCH and a given drug (MDI) can be extrapolated to other MDIs, even for members of its particular drug class. The procedure outlined in The United States Pharmacopeia–The National Formulary was used (determination of canister weight changes after actuation). The SP/HCH tested were Aerochamber^®, Inspirease^®, and ACE^®. The MDIs tested were salmeterol xinafoate; albuterol with chlorofluorocarbons and 1,1,1,2-tetrafluoroethane as propellants; cromolyn sodium; nedocromil sodium; flunisolide; beclomethasone dipropionate; and fluticasone propionate. Only flunisolide-Inspirease^® presented an unacceptable MP. Although within the acceptable limits, the MP varied significantly between the following MDI-SP/HCH combinations: Optihaler^®–fluticasone propionate and Optihaler^®–cromolyn sodium < to Aerochamber^®–fluticasone propionate and Aerochamber^®–cromolyn sodium (p = 0.0015 and p = 0.0007, respectively); and Inspirease^®–flunisolide and Optihaler^®–flunisolide < Aerochamber^®flunisolide (p = 0.003 and p = 0.005, respectively). MP did not significantly vary when albuterol with chlorofluorocarbons or 1,1,1,2-tetrafluoroethane as propellants, salmeterol xinafoate, beclomethasone dipropionate, and nedocromil sodium were attached to any of the SP/HCHs studied. Our results emphasize the capital importance of choosing the right combination of MDI and SP/HCH for aerosol delivery. The MP obtained with a drug and a SP/HCH cannot be expected to be similar for other MDIs, even for members of its drug class. These data also suggest the need for regulatory agencies to approve an MDI to be used only with the SP/HCHs tested.

Relatively little is known about the variables that influence lung deposition of inhaled aerosols in children. A model of the upper airways of an infant could be a useful tool to study these variables in vitro. The objective of this study was to construct an anatomically correct model of the upper airways of a young child. A routine three-dimensional (3D) CT scan of the skull and neck of a child was selected that included the airway from the nasal cavity down to the subglottic region. The CT scan was edited to obtain an anatomically correct distinction between air and mucosa. Next, a model was constructed with a stereolithographic technique using a UV-sensitive resin. To validate the model, a 3D CT scan of the model was made and compared to the anatomy of the original image. To study aerosol deposition, the model was connected to a breathing simulator. Medical aerosols were delivered to the model by MDI/spacer during stimulated breathing. An upper airway model was made of a 9-month-old child that needed reconstructive surgery for a skull deformity and with normal anatomy of the upper airways. The nasal airway of the model was open for air passage and the oral airway was closed. The CT scan of the model matched the original in vivo CT scan closely. Aerosol deposition measurements showed that dose passing the model, or lung dose, was comparable with in vivo lung deposition data. We have constructed an anatomically correct model of the upper airways of a child, using a stereolithographic method for in vitro studies of aerosol deposition in young children. This model will be used to obtain insight in aerosol treatment that cannot be obtained in vivo.

The efficacy of inhaled pharmaceuticals depends, in part, on their site of respiratory deposition. Markedly nonuniform ventilation distribution may occur in persons with obstructive airways diseases and may affect particle deposition. We studied the relationship between regional deposition (RDep) and regional ventilation (RVent) in a group of 12 cystic fibrosis (CF) patients with mild to moderate airway obstruction (63 ± 8% predicted FEV₁) and 11 healthy nonsmoking volunteers (104 ± 13% predicted FEV₁) using planar scintigraphic methods. RDep was assessed from initial deposition and 24-h retention images for monodisperse technetium-99m–labeled iron oxide particles (5-μm MMAD). Regional volumes and RVent were assessed from xenon-133 equilibrium and washout, respectively. Six regions of interest per lung were established by dividing each lung into thirds by height and approximately half by width. The two lower regions of the left lung were not analyzed due to activity in the stomach. Remaining regions were categorized as central (two interior-most regions) and peripheral (eight exterior regions). RDep and RVent were computed for the eight peripheral regions. Tracheobronchial (TB) deposition was estimated for each of the peripheral regions as the difference between initial activity and decay-corrected 24-h retention or parenchymal deposition. RDep was computed as the fraction of material within a region normalized to regional volume. RVent for each region was determined by normalizing the xenon washout rate for that region by the total washout rate for the eight peripheral regions. Significant linear associations were found between RDep and RVent in both the healthy subjects and CF patients. In healthy subjects, RDep in the TB airways was positively associated with RVent (p = 0.03). In CF patients, RDep in the TB airways was negatively associated with RVent (p = 0.04) and RDep in the parenchyma was positively associated with RVent (p < 0.001). The initial pattern of RDep in the lung was not significantly associated with RVent in either group. These data suggest that significant coarse particle deposition may occur in the TB airways of poorly ventilated lung regions in CF patients, whereas, particle deposition in the TB airways of the healthy subjects follows ventilation.

Interactions between selected toxic aerosols and gases occurring in the air at the workplace and the pulmonary surfactant (PS) have been studied with two physicochemical techniques in vitro. The Pulsating Bubble Surfactometer (PBS) and the Langmuir-Wilhelmy Balance (LWB) have been used for measurements of dynamic interfacial properties of the PS material after its contact with several gases (sulfur dioxide, nitrogen oxides, ozone, ammonia) and liquids (sulfuric, nitric and hydrochloric acids and ammonium hydroxide), which can be brought into the alveoli with the inhaled air. Surface tension–area relationships for the interface oscillations have been analyzed using qualitative criteria of normalized hysteresis area (HA_N) and minimum surface tension (σ_min). It was demonstrated that, for each analyzed compound, inactivation of the surfactant occurs, but the critical concentrations and doses are compound specific, which suggests the toxic potential of the investigated substances with respect to PS. Possible mechanisms of the interactions between the investigated substances and the surfactant components are discussed. Degradation of the PS dynamical interfacial properties (HA_N and σ_min), important from the physiological viewpoint, observed in our in vitro experiments, suggests a possibility of adverse health effect in the case of a chronic inhalation of toxic gases and aerosols, even at low concentration or after a short exposure to strongly contaminated air. It results in a slowdown of the pulmonary clearance rate and increase of the lung burden for both considered cases.

The objective of this study was to evaluate relative efficiency in vitro of four reusable breath-enhanced nebulizers (Pari LC Star, Medic-Aid Ventstream, Devilbiss PermaNeb, Salter Ultramist), and to integrate the in vitro performance data of the nebulizers with the respiratory patterns of four cystic fibrosis (CF) patients to compare efficiency in vivo of each device for each individual patient. Six nebulizers of each type were used to nebulize a solution of 2.5 mg (0.5 mL) albuterol with 3.5 mL of 0.9% saline. Total albuterol output and the rate of albuterol output of each device were measured until end-nebulization and for 4 min, respectively, using entrained flows from 0 to 20 L/min through the inspiratory valve of the device. Particle size distributions and the respirable fraction (RF) were evaluated by laser diffraction technique. Regression analysis of the change in rate of output and change in RF values with inspiratory flows was done to characterize each nebulizer's performance over the complete range of interest. Actual breath tracings of four CF patients were integrated with the equations specific to the in vitro performance of each nebulizer and in vivo nebulizer efficiency was calculated. The change in efficiency in vitro from 0 to 20 L/min flow, respectively, was highest for the Star (44–57%) and lowest for the Ultramist (13–15%). The mean predicted efficiency in vivo for the Star was threefold that of the Ultramist. Although all four nebulizers are breath-enhanced in design, clearly there are measurable differences in the performance and efficiency of each type. The Pari LC Star nebulizer has proven to be the nebulizer of choice among the devices tested.

Respiratory spacer devices are used mainly with pressurized metered dose inhalers, especially those containing corticosteroids, to assist with patient coordination and reduce oropharyngeal side effects. This investigation examines the influence of different spacer devices on the delivered fine particle mass (aerodynamic diameter of <3.3 μm and <4.7 μm) of the corticosteroid beclomethasone dipropionate, which approximates the respirable dose. The Anderson Mark II Cascade Impactor was used to characterise the deposition of single doses of beclomethasone dipropionate from several metered-dose inhalers. Following actuation of one single dose the amount of beclomethasone dipropionate deposited on each stage of the impactor was quantified using reverse phase high-performance liquid chromatography and ultraviolet detection. The fine particle mass smaller than 4.7 μm for Respocort^® delivered by the Sanner^® and Fisonair^® spacer devices was 77.7% and 41.3% higher (p < 0.04), respectively, than the metered-dose inhaler alone, while the Breathatech^® spacer delivered 21.4% lower (p < 0.01). The fine particle mass of Becotide^® delivered by the Sanner^®, Fisonair^®, Nebuhaler^®, and Volumatic^® spacer devices were 81%, 42.4%, 46.9%, and 32.8% higher (p < 0.008), respectively, than be metered dose inhaler alone. The fine particle mass for Becloforte^® delivered by the Sanner^®, Fisonair^®, and Volumatic^® spacer devices was 82.8%, 36.9%, and 48.0% higher (p < 0.009) than that delivered by metered dose inhaler alone. This study suggests that there are significant differences in the fine particle mass of beclomethasone dipropionate delivered by respiratory spacer devices when used in conjunction with commercially available metered dose inhalers of this drug.

The mometasone furoate dry powder inhaler (MF-DPI) is a multiple-dose, breath-actuated inhaler that uses agglomerates of micronized MF and lactose. In vitro analyses evaluated dose uniformity, variability, and particle size distribution of the MF-DPI. Tests of first, middle, and end doses from 10 inhalers each of the 200-μg MF/inhalation and 400-μg MF/inhalation dose sizes found that delivered doses (doses emitted from the inhaler) ranged from 91% to 112% of claimed doses for all tested DPIs. The mean MF doses delivered at 28.3 L/min were 100% and 94% of the doses delivered at 60 L/min for the 200-μg and 400-μg dose sizes, respectively; the relative standard deviation of doses was ≤ 6.1% within this range of inhalation rates. At a flow rate of 60 L/min, the mean delivered doses, compared to claimed doses for inspiration times of 1–3 sec, were 102–104% for the 200-μg dose size and 98.8–102% for the 400-μg dose size. The mean cumulative fraction of dose delivered at 60 L/min for 2 sec which consisted of particles of < 6.5 μm in diameter was 39.9% (± 2.5 SD; n = 9) for the 200-μg dose size and 35.6% (± 3.4 SD; n = 9) for the 400-μg dose size. All MF-DPI inhalers tested were well within U.S. and European compendial standards and regulatory guidelines for dose uniformity. An appropriate and reproducible fraction of the delivered dose was within the optimal particle size range for therapeutic effectiveness.

Dry powder inhalers for eformoterol fumarate dihydrate, a long-acting beta-2 agonist for bronchodilation, are currently available as the Foradile^® Aerolizer^® and the Oxis^® Turbuhaler^®. The two products are different in the formulation, the aerosol production mechanism, and the device resistance to air flow. These disparities are likely to lead to different aerosol characteristics. Our objective was to compare the in vitro performance of these two inhalers in producing eformoterol aerosols. Emitted dose uniformity was measured using a sampling apparatus described in the British Pharmacopaeia. Ten individual doses (dose number 2, 3, 15, 16, 30, 31, 45, 46, 59, and 60) of the entire content (60 doses) were collected from the Aerolizer^® and the Turbuhaler^® (six inhalers each). Particle size distribution of the aerosols generated by the two inhalers were measured by a multiple stage liquid impinger at four different air flows (30–120 L/min). Eformoterol collected from the sampling devices was measured by HPLC. Fine particles are those of ≤1.7–5.0 μm in size in the aerosols obtained by interpolation of the data at the specified air flow. The Aerolizer^® showed a slight dependence of the emitted dose on the air flow, with the average emitted dose increased from 80% (at 30 L/min) to 90% (at higher flows) of the 12-μg label claim as compared with 60% for the Turbuhaler^®. When the emitted dose was normalized by the average emitted dose value, the Aerolizer^® showed less variation in the normalized emitted dose uniformity than the Turbuhaler^®. At high air flows, 90 and 120 L/min, both inhalers produced similar amounts (4 μg) of fine particles in the aerosol per dose discharged. As the flow as decreased to 30 and 60 L/min, both inhalers produced significantly less fine particles (p < 0.05), with the Oxis^® Turbuhaler^® producing lesser amounts than the Foradile^® Aerolizer^®. However, due to the different device resistance, comparing the inhaler performance at the same inspiratory effort may be more appropriate. At a comfortable effort of 40 cm H₂O, the Foradile^® Aerolizer^® would produce a significantly higher fine particle mass in the aerosols. We conclude that the two inhalers were dissimilar in the emitted dose uniformity. The fine particle mass of eformoterol produced by the two inhalers was equivalent at high but not at low air flows. The disparities may be due to the difference in the formulation and the aerosol generation mechanism of the inhalers.