Targeting aerosol deposition in patients with cystic fibrosis: effects of alterations in particle size and inspiratory flow rate.

STUDY OBJECTIVE: To determine if aerosolized medications can be targeted to deposit in the smaller, peripheral airways or the larger, central airways of adult cystic fibrosis (CF) patients by varying particle size and inspiratory flow rate. DESIGN: Randomized clinical trial. SETTING: Outpatient research laboratory. PATIENTS: Nine adult patients with CF. INTERVENTIONS: Patients inhaled an aerosol comprised of 3.68+/-0.04 microm saline solution droplets (two visits) or 1.01+/- 0.2 microm saline solution droplets (two visits) for 30 s, starting from functional residual capacity and breathing at a slow or faster inspiratory flow rate. On all visits, the saline solution was admixed with the radioisotope (99m)Tc. Immediately after inhalation, a gamma camera recorded the deposition pattern of the radioaerosol in the lungs. Deposition images were analyzed in terms of the inner:outer zone (I:O) ratio, a measure of deposition in an inner zone (large, central airways) vs. an outer zone (small airways and alveoli). MEASUREMENTS AND RESULTS: For the 3.68-microm aerosol, I:O ratios averaged 2.29+/-1.45 and 2.54+/-1.48 (p>0.05), indicating that aerosol distribution within the lungs was unchanged while breathing at 12+/-2 L/min vs. 31+/-5 L/min, respectively. For the 1.01-microm aerosol, I:O ratios averaged 2.09+/-0.96 and 3.19+/-1.95 (p<0.05), indicating that deposition was predominantly in the smaller airways while breathing at 18+/-5 L/min and in the larger airways while breathing at 38+/-8 L/min, respectively. CONCLUSIONS: These results suggest that the targeted delivery of an aerosol to the smaller, peripheral airways or the larger, central airways of adult CF patients may be achieved by generating an aerosol comprised of approximately 1.0-microm particles and inspiring from functional residual capacity at approximately 18 L/min and approximately 38 L/min, respectively.

Evaluation of aerosol drug output from the OptiChamber and AeroChamber spacers in a model system.

Metered-dose inhalers (MDIs) are an effective means of generating drug-containing aerosols targeted for delivery to intrapulmonary airways. Many problems associated with incorrect patient use of MDIs are mitigated by adding a valved spacer device to the inhaler mouthpiece. This in vitro study compared the efficiency of drug output through a new spacer device, OptiChamber (HealthScan Products Inc., Cedar Grove, NJ), to that of a device commercially available since the 1980s, AeroChamber (Monaghan Medical, Plattsburgh, NY). Testing utilized MDI formulations of albuterol, beclomethasone dipropionate, and cromolyn sodium. OptiChamber equaled or, in the majority of cases, exceeded AeroChamber in output of the three drugs at two simulated inspiratory flow rates. Drug output from OptiChamber was found to be less sensitive to changes in flow rate than that from AeroChamber. OptiChamber also showed less decrease in drug output than AeroChamber when time delays were introduced between MDI actuation and the start of a simulated inhalation. Mass median aerodynamic diameters of drugs exiting the two spacers were generally similar to those of drugs exiting the MDI alone. However, spacers were shown to nearly eliminate the output of large-size drug particles (>5.8 microm), which can result in oropharyngeal drug deposition. Emitted fine-particle drug (<5.8 microm) doses from OptiChamber were greater than those from AeroChamber with or without a delay between canister actuation and the start of a simulated inhalation. The results suggest that OptiChamber may provide more efficacious aerosol drug delivery than AeroChamber under both ideal and suboptimal conditions.

The efficacy of slow versus faster inhalation of cromolyn sodium in protecting against allergen challenge in patients with asthma.

BACKGROUND: Approximately one third of patients with allergy-induced asthma who are treated with aerosolized cromolyn sodium (CS) fail to achieve a full therapeutic effect. This lack of effectiveness could involve nonhomogeneous distribution of drug in the lung as a result of high inspiratory flow rates. OBJECTIVE: We sought to determine the efficacy of slow versus faster inhalation of CS in protecting against allergen challenge in patients with asthma. METHODS: Eight patients with asthma underwent two allergen challenges 30 minutes after pretreatment with CS that was inhaled from a large holding chamber at approximately 30 L/min or approximately 70 L/min. Percent decreases in FEV1 at a common dose of allergen on the two challenge days were compared. Values of skew (an indicator of aerosol distribution homogeneity) obtained from gamma camera lung images after slow and faster inhalation of radiolabeled CS were also compared. RESULTS: Mean (+/- SD) allergen-induced decrease in FEV1 was 5.4% +/- 4.2% after slow inspiration of CS, which was significantly less than the allergen-induced decrease in FEV1 after faster inhalation of CS with 12.6% +/- 11% (p < 0.05). Mean skew values were also significantly decreased after slow inspiration of CS, and differences in decreases in allergen FEV1 and skew values for the two breathing maneuvers were significantly correlated. CONCLUSION: These data indicate that protection against allergen-induced asthma can be optimized by slowly inspiring CS from a large holding chamber compared with faster inhalation of the drug. These results appear to be related to enhanced distribution homogeneity of CS within the lungs.

Comparison of a respiratory suspension aerosolized by an air-jet and an ultrasonic nebulizer.

In the absence of USP standards and performance monographs, this research sought to determine if differences in the aerosolization mechanism (air-jet vs. ultrasonic) affected droplet and insoluble particle deposition of a nebulized model respiratory suspension. Five milliliters of a model suspension containing 0.1% w/v fluorescein (to estimate droplet deposition) and known quantities of 1, 3, and 6 microns latex spheres (representing insoluble drug particles) was aerosolized from an air-jet and an ultrasonic nebulizer. Nebulized output was collected in a modified Andersen impactor. Samples were analyzed spectrophotometrically (490.5 nm) and by a Coulter Counter to estimate droplet and sphere deposition, respectively. The distribution of droplets throughout the modified impactor for both nebulizers suggested that both the air-jet and the ultrasonic nebulizer produced droplets (0.4 to 10 microns in aerodynamic diameter) large enough to incorporate 1, 3, and 6 microns insoluble spheres. However, Coulter Counter analysis of the sphere distribution revealed that while the air-jet nebulized output contained spheres of all sizes, this was not true for the ultrasonic nebulizer. In the ultrasonic nebulizer, 99% of the spheres (irrespective of size) were not aerosolized and were recovered from the nebulizer reservoir at the aerosolization end point. The results highlight the importance of evaluating performance of a respiratory suspension in combination with a specific nebulizer. When conducting in vitro inertial deposition testing of a respiratory suspension, it is inappropriate to assume that deposition trends of droplets will predict the deposition of the insoluble dispersed phase.

Preparation, characterization, and dissolution kinetics of two novel albuterol salts.

The possibility of producing slowly dissolving albuterol salts was investigated as a potential means of extending the duration of action of the drug following aerosol delivery to the lung. Albuterol adipate and stearate were precipitated from alcoholic solutions of albuterol and adipic or stearic acids, respectively. Differential scanning calorimetry and hot stage microscopy showed that albuterol adipate and stearate produced single melting endotherms at 182 and 116 degrees C, respectively, which were distinct from those of albuterol (158 degrees C), adipic acid (152 degrees C), and stearic acid (70 degrees C). The aqueous solubilities of albuterol free base, sulfate, adipate, and stearate were 15.7, 250, 353, and 0.6 mg . mL-1, respectively, at room temperature. Only the solubilities of the adipate and the stearate increased significantly when the temperature was elevated to 37 degrees C (452.5 and 1.4 mg . mL-1, respectively). With a rotating disk dissolution method, albuterol free base, sulfate, and adipate were found to have intrinsic dissolution rates of 1.1, 20.4, and 24.0 mg . min-1 . cm-2, respectively, in pH 7.4 phosphate buffer at 37 degrees C. Albuterol stearate dissolved much more slowly and in a nonlinear fashion; this was explained by the deposition of a stearate-rich layer on the dissolving surface of the compacted salt.

Prediction and assessment of flammability hazards associated with metered-dose inhalers containing flammable propellants.

Several potential replacements for chlorofluorocarbons (CFCs) in metered-dose inhalers (MDIs) are flammable. The flammability hazard associated with their use was assessed using a range of MDIs containing 0-100% (w/w) n-butane (flammable) in HFC-134a (non-flammable) fitted with either 25-, 63-, or 100-microliters metering valves or continuous valves. In flame projection tests each MDI was fired horizontally into a flame, and the ignited flume length emitted from the MDI was measured. Flame projections of greater than or equal to 60 cm were produced by all formulations fitted with continuous valves which contained greater than or equal to 40% (w/w) n-butane in HFC-134a. Using metering valves the maximum flame projection obtained was 30 cm. This was observed with a formulation containing 90% (w/w) n-butane in HFC-134a and a 100-microliters valve. For a particular formulation, smaller metering valves produced shorter flame projections. Because many MDIs are used in conjunction with extension devices, the likelihood of accidental propellant vapor ignition was determined in Nebuhaler and Inspirease reservoirs and a Breathancer spacer. Ignition was predictable based on propellant composition, metered volume, number of actuations, and spacer capacity. Calculated n-butane concentrations in excess of the lower flammability limit [LFL; 1.9% (v/v)] but below the upper flammability limit [UFL; 8.5% (v/v)] were usually predictive of flammability following ignition by a glowing nichrome wire mounted inside the extension device. No ignition was predicted or observed following one or two 25-microliters actuations of 100% n-butane into large volume Nebuhaler (750 ml) or Inspirease (660 ml) devices.(ABSTRACT TRUNCATED AT 250 WORDS)

Optimized inhalation aerosols. I. The effects of spherical baffle size and position upon the output of several pressurized nonaqueous suspension formulations.

Baffles contained in conventional actuators may be a convenient alternative to some of the extension devices used presently with metered-dose inhalers (MDIs). Actuators were modified to determine whether baffles could be used to decrease the output of large "nonrespirable" droplets. These actuators were tested using a series of nonaqueous suspension aerosols containing 0.1 to 2.0% micronized disodium fluorescein (DF) as the model drug, stabilized by sorbitan trioleate in a constant blend of fluorocarbons 11, 12, and 114. A 25-microliter metering volume was used throughout. Aerosol output was characterized by cascade impaction. Baffle size and position had pronounced effects on actuator retention and aerosol output. Increasing baffle size resulted in increased retention in the actuator. The total output of the MDI in the "respirable" range (aerodynamic diameter, Dae, less than 5.5 microns) was greater in the unbaffled actuator than in all baffled actuators. However, all baffles increased the respirable fraction (DF with Dae less than 5.5 microns: total DF leaving the actuator), R, when compared to their unbaffled controls. For example, for a 0.1% DF, 0.14% surfactant formulation, R was increased from 0.40 (unbaffled) to 0.71 by incorporation of a 0.6-cm-diameter sphere 1.3 cm from the jet of the actuator. In these cases, aerosol segregation occurred due to droplet inertia in the high velocity gas flows. Increasing the respirable fraction at the expense of the total respirable output may obviate undesirable clinical effects.

Comparison of output particle size distributions from pressurized aerosols formulated as solutions or suspensions.

The delivery of particles as small as possible (preferably less than 5 microns) to the respiratory tract should be the aim of those formulating metered dose inhalers (MDIs). This may be facilitated by the formulation of solution, rather than suspension-type, pressurized aerosol units. Two series of MDIs were compared; one contained suspended micronized disodium fluorescein (0.1%, w/v), while the other contained the same concentration of dissolved salicylic acid. Either oleic acid, L-alpha-phosphatidylcholine, or sorbitan trioleate was incorporated at 0.15% (w/v) as suspending agent (disodium fluorescein) or solubilizing agent (salicylic acid). The propellant blend was 70% (w/w) Freon 12 and 30% (w/w) Freon 11 in all cases. This exhibited a vapor pressure of 50.6 psig (444.7 kPa) at 21 degrees C. The output particle size distribution of the aerosol reaching the cascade impactor showed a mass median aerodynamic diameter (MMAD) of approximately 4 and 2 microns for the suspension and solution formulations respectively, regardless of the surfactant used. Larger MMADs were observed for solution aerosols formulated with oleic acid (2.32 microns) compared to those containing L-alpha-phosphatidylcholine (1.93 microns) or sorbitan trioleate (2.07 microns). Possible reasons for these observations are discussed.

Effects of heat treatment on the permeability of polyvinyl alcohol films to a hydrophilic solute.

Polyvinyl alcohol (PVA) films may be useful as release-controlling membrane systems. Untreated, they are readily permeable to water and hydrophilic drugs. Because heating has been used to increase crystallinity and thus reduce the solubility and swelling in water of PVA films, we have studied the effects of heat on the permeability of PVA films to a water-soluble drug marker. Heat treatment was varied in the temperature range 100-200 degrees C for 1 h. The effect of time of heating was studied at 100 degrees C for 0.5-160 h. After pre-equilibration with water (heat-treated membranes remained intact, untreated ones dissolved), membrane permeabilities to methylene blue in aqueous solution (37 degrees C) were determined in a rotating diffusion cell. Permeabilities decreased with increased heating times (0.98-0.039 cm X min-1 for 0.5-160 h at 100 degrees C, respectively). Heating in air or N2 produced similar results. Further dramatic decreases in permeability occurred with increasing pretreatment temperatures; membrane permeability fell by a factor of approximately 500 with increasing temperature in the range 100-200 degrees C. There was no evidence of decomposition at temperatures less than or equal to 190 degrees C for 1 h. Results were consistent with literature reports of heat-induced increases in crystallinity. Membranes were simple to prepare and permeability could be controlled without recourse to chemical manipulation.