Bench testing of nebulizers: a comparison of three methods.

Although nebulizers can vary widely in performance, there is no uniformly accepted method for bench testing these devices. In the present study, we compared three bench methods of measuring the performance of three commercial jet nebulizers (Whisper Jet [WJ; Marquest Medical, Englewood, CO], Sidestream [SS; Marquest Medical], and Vixone [VO; Westmed, Tucson, AZ] to assess the impact of the method of testing on reported nebulizer performance. Each nebulizer was charged with 3 mL of albuterol mixed with a radiotracer (technetium [99mTc]), and the radioactivity captured on a paper filter was expressed as a percentage of the nebulizer charge (% delivered). The nebulizers were tested with and without duplication of spontaneous respiration by a piston pump (spontaneous respiration and standing cloud methods, respectively). The nebulizers were also tested using a model of mechanical ventilation (mechanical ventilation method). For all three devices, the addition of the standardized breathing pattern significantly reduced the % delivered with all three nebulizers compared with the standing cloud method. For the standing cloud method, the presence of the T-piece/mouth-piece significantly reduced the % delivered with the WJ but not with the other two devices. The mechanical ventilation method had the lowest % delivered for all three devices. The magnitude of the differences between nebulizers varied with duration of treatment. The findings of this study emphasize the importance of bench testing that duplicates intended clinical usage, because significant differences in nebulizer performance may be manifested under certain clinical conditions but not under others.     

Measurement of particle and mass distribution of pentamidine aerosol by ultrasonic and air jet nebulizers.

The use of appropriate nebulizers is a major precondition for a successful treatment and prevention of Pneumocystis carinii pneumonia with pentamidine aerosol. The apparatus should supply a sufficient amount of pentamidine with adequate particle size. Using Fisons ultrasonic nebulizer FISO Neb, model FZV 40 BAMKI, De Vilbiss ultrasonic nebulizer, Porta-Sonic, model 8500 GB, and the Marquest Medical Products jet nebulizer Respirgard II, two pentamidine concentrations (300 mg/6 ml and 60 mg/6 ml) were compared by measuring nebulized pentamidine mass distribution and particle size distribution under in vitro conditions by means of a laser light-scattering particle sizer of the type Malvern Master sizer. It was found that there were significant differences among nebulizers. Mass distribution experiments with air flow 6 l/min showed that using FISO Neb the quantity of nebulized pentamidine was 201.4 mg and 36.7 mg, whereas using Porta-Sonic the values found decreased to 85.2 mg and 23.6 mg. Using Respirgard II the values were 80.0 mg and 10.64 mg. The measured total duration times of nebulization were 6 - 8.5 min, 12 min and 25 min for the nebulizers FISO Neb, Porta-Sonic and Respirgard II. A decomposition of pentamidine during nebulization in the case of ultrasonic nebulizers doesn't take place. The measured mass median diameters (MMD) were 5.6 - 6.9 mum, 1.96 - 3.04 mum and 1.9 - 2.5 mum for the nebulizers FISO Neb, Porta-Sonic and Respirgard II. Using 300 mg pentamidine the nebulized amounts of pentamidine containing particles sizes less than or equal to 2 mum predominately available for alveolar deposition were with values of about 43 mg markedly higher for Respirgard II and Porta-Sonic than the measured 10.5 mg for FISO Neb.     

Bolus inhalation of rhDNase with the AERx system in subjects with cystic fibrosis.

Inhaled recombinant human deoxyribonuclease (rhDNase) delivered by nebulizer improves pulmonary function and reduces the rate of pulmonary exacerbations in cystic fibrosis subjects. Standard jet nebulizers are relatively inefficient and require a delivery time of 10-20 min. We conducted an open-label, proof-of-concept study to evaluate whether bolus inhalation of rhDNase with a more efficient delivery system was safe and effective in cystic fibrosis subjects. The AERx system used for this study aerosolized 1.35 mg of rhDNase in three inhalations at a single sitting. The predicted AERx lung dose was approximately 0.68 mg, a dose consistent with lung doses of rhDNase given by jet nebulizer. In our 16 subjects with cystic fibrosis, a mean relative increase in FEV(1) of 7.8% (p < or = 0.001) was observed after 15 days of bolus delivery of rhDNase with the AERx system. The safety profile of rhDNase given as a bolus was similar to that observed with traditional nebulizer delivery. This study demonstrated that bolus inhalation of rhDNase was feasible, reasonably well-tolerated, and associated with improvement in pulmonary function in this small group of cystic fibrosis subjects.     

Inhaled azithromycin therapy.

The treatment of pulmonary infectious diseases with pharmaceutical aerosols is an attractive option considering the accessibility of the lungs for topical drug delivery. Aerosols have been targeted to the lungs for the treatment of asthma with great success. Current therapies for other diseases, including Pseudomonas aeruginosa, Pneumocystis jirovecii (formerly Pneumocystis carinii), and mycobacterial infections, remain suboptimal due to the efficacy/safety profile. This may be improved by aerosol targeted pulmonary drug delivery. Azithromycin is a broad spectrum antibiotic that acts by inhibiting protein synthesis. It is associated with side effects that might be avoided by aerosol delivery to the lungs. In the present study three concentrations of azithromycin (10, 50, and 100 mg/mL) were delivered from three nebulizers (Acorn II, Updraft, and LC Plus) operated at 8 L/min. Particles size analyses were conducted by inertial impaction and laser diffraction. In addition, emitted doses were determined. A linear proportionality existed across the concentration range between nominal dose and both fine particle dose/fraction and emitted dose, with R2 > 0.999 in all cases. The mass median aerodynamic diameter increased from 1.4 to 1.9 microm between 10 and 100 mg/mL of azithromycin solution concentration for the Acorn II. The particle size distributions were not all log-normally distributed. The median particle size delivered from the devices was largest for the Updraft (2.8 microm) and smallest for the Acorn II (1.9 microm) for 100 mg/mL azithromycin solution concentrations. The efficiencies of small particle delivery (%<4.7 microm) were as follows, LC Plus = Acorn II (85%) > UpDraft (75%). However, the emitted dose from the LC Plus (55 mg/min) was higher than the Acorn II (31 mg/min) to maximize lung exposure to the aerosol, small median diameters and broad particle size distributions would be most effective. This study demonstrates that the dose delivered to the lungs will be maximized, under the current operating conditions by adopting the LC Plus, and high (100 mg/mL) azithromycin concentrations.     

Liquid atomizing: nebulizing and other methods of producing aerosols.

Liquid atomization (or nebulization) is the most traditional method of drug delivery to the lung. Although other methods seem to often be preferred for the delivery of new drugs, nebulizers are experiencing a revival, with new devices based on different atomization techniques, and the more traditional jet nebulizers evolving to become "smart nebulizers." These smart devices synchronize delivery with the patient's breath, estimate or measure delivered dose, provide feedback and data storage, and in some cases control breathing maneuvers. Besides adding new features, new nebulizers are also addressing traditional shortcomings, namely, reducing size, bulkiness, and power consumption. But in the longer term, nebulizers are expected to offer even more important features. Following the trend toward individually optimized therapy, nebulizers will be able to estimate deposited dosage and concentrations in the lung. In addition, as progress in nanotechnology allows the development of smart drug carrying particles, advanced liquid nebulization is expected to be the delivery mode of choice for these smart particle aerosols.     

Determination of nebulizer droplet size distribution: a method based on impactor refrigeration.

Size distributions of droplets generated by nebulizers are difficult to determine because of evaporation after aerosolization. We describe a method whereby a Next Generation Pharmaceutical Impactor (NGI; MSP Corporation, Shoreview, MN) is refrigerated at 5 degrees C before connecting it to the nebulizer in order to ensure an environment inside the NGI at close to 100% relative humidity (RH). This, in turn, reduces droplet evaporation between the nebulizer and impaction. The method development was performed with a Pari LC Plus jet nebulizer operated at 2.0 bar, with the NGI set at a flow rate of 15 L/min and with salbutamol 5.0 mg/mL as the test solution. The droplet size distributions were expressed in terms of mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD). Variation in test conditions showed that the NGI should be cooled for at least 90 min, that nebulization should be started within 5 min after removal from the refrigerator, and that coating of collecting cups to prevent "bouncing" is not necessary. Variation of ambient temperature and humidity had no relevant effect on results. MMAD and GSD results showed that refrigeration of the NGI resulted in droplet size distributions that are likely to reflect those originally delivered at the mouthpiece by the nebulizer. The method was shown to be robust, accurate with recovery of test solutions exceeding 99%, reproducible, and to be suitable for use with a wide range of commercially available nebulizers.     

The effects of Heliox on the output and particle-size distribution of salbutamol using jet and vibrating mesh nebulizers.

There are theoretical benefits of delivering drug aerosols to patients with asthma and chronic obstructive pulmonary disease (COPD) using Heliox as a carrier gas. The objective of this study was to develop systems to allow bronchodilators nebulized by a breath enhanced jet nebulizer and a vibrating mesh nebulizer to be delivered to patients in Heliox. This was achieved by attaching a reservoir to the nebulizers to ensure inhaled Heliox was not diluted by entrained air. For the vibrating mesh nebulizer, the total output was significantly higher after 5 min of nebulization when Heliox rather than air was used as the delivery gas (p < 0.001). The proportion of drug in particles <5 microm was 58.1% for Heliox and 50.1% when air was entrained. When the breath enhanced nebulizer was used a much higher driving flow of Heliox, compared to air, was required to deliver a similar dose of drug (p < 0.05). The total amount of drug likely to be inhaled was significantly higher when the vibrating mesh nebulizer (Aerogen) was used compared to the breath enhanced jet nebulizer (Pari LC plus) (p < 0.001). The amount of drug likely to be inhaled was also significantly greater for the adult as opposed to pediatric breathing pattern for all nebulizers and flows tested with the exception of the Aeroneb and Heliox entrainment. In this case, total amounts were similar for both patterns but for the pediatric pattern, the time taken to reach this output was longer. Such information is required to allow appropriate interpretation of clinical trials of drug delivery using Heliox.     

Inhalation of tobramycin in cystic fibrosis. Part 1: the choice of a nebulizer.

Forteen commercially available jet and ultrasonic nebulizers were investigated with the aim to select the most suitable type of apparatus for the inhalation of a 10% tobramycin solution. Two different techniques for measurement of particle size distribution were evaluated: laser diffraction and cascade impactor analysis. The final selection of the nebulizers is based on particle size distribution, output and stable performance during nebulization. All 14 nebulizers (eight jet and six ultrasonic) were filled with a solution of 10% m/v tobramycin (as sulphate) in water. The volume in the tested devices ranged from 4.5 to 10 ml (=450-1000 mg tobramycin) in accordance with the prescribed usage by the suppliers. The nebulizers were connected with a special designed adapter to a laser diffraction analyser in order to measure particle size distribution of the aerosol. Inhalation was simulated with a static flow of 40 l/min. The particle size distribution (expressed as X(10), X(50), and X(90)) was determined after 10 s, 1.5, 3, 4.5, 6, 9 and 12 min of nebulization. Furthermore, the tobramycin solutions were assayed for tobramycin content before and after nebulization. For all nebulizers, the mean particle size distribution, depicted as X(50), was within the range of 1-5 mm. There were no relevant differences between the nebulizers in concentration or particle size distribution during nebulization. The output of the nebulizers is a result of both nebulization and evaporation. The output, expressed as volume of tobramycin solution, ranged from 0.06 to 0.50 ml/min. The output of tobramycin ranged from 1.2 to 39.5 mg/min. For clinical practice 300-600 mg have to be nebulized within 20-30 min. It was concluded that only three jet nebulizers [Porta-Neb Sidestream (PNS), Porta-Neb Ventstream (PNV) and Pariboy Pari LC+ (PLC)] have a reasonable output and an acceptable particle size distribution for the administration of a 10% tobramycin solution in the therapeutic dosage range.     

Nebulizers for drug delivery to the lungs

Introduction: Nebulizers are the oldest modern method of delivering aerosols to the lungs for the purpose of respiratory drug delivery. While use of nebulizers remains widespread in the hospital and home setting, certain newer nebulization technologies have enabled more portable use. Varied fundamental processes of droplet formation and breakup are used in modern nebulizers, and these processes impact device performance and suitability for nebulization of various formulations.

Areas covered: This review first describes basic aspects of nebulization technologies, including jet nebulizers, various high-frequency vibration techniques, and the use of colliding liquid jets. Nebulizer use in hospital and home settings is discussed next. Complications in aerosol droplet size measurement owing to the changes in nebulized droplet diameters due to evaporation or condensation are discussed, as is nebulization during mechanical ventilation.

Expert opinion: While the limelight may often appear to be focused on other delivery devices, such as pressurized metered dose and dry powder inhalers, the ease of formulating many drugs in water and delivering them as aqueous aerosols ensures that nebulizers will remain as a viable and relevant method of respiratory drug delivery. This is particularly true given recent improvements in nebulizer droplet production technology.     

In vitro deposition properties of nebulized formoterol fumarate: effect of nebulization time,airflow, volume of fill and nebulizer type

ABSTRACT

Objective: The aim of this study was to investigate in vitro the delivery of a new long-acting β₂-agonist (LABA) drug formoterol fumarate inhalation solution (20?µg/2?mL) nebulized with and without ipratropium bromide (0.5?mg/2.5?mL) at different administration times (2.5–22.5?min), airflows (5–28.3?L/min), nebulizer fill volumes (2–6?mL), and nebulizer brands (Pari LC+, Ventstream and DeVilbiss).

Method: Formoterol fumarate with and without ipratropium bromide was aerosolized at different administration times, airflows, nebulizer fill volumes, and nebulizer brands. The drug deposited on the throat, filter and stage plates was collected and analyzed by HPLC to determine the aerodynamic profiles of the nebulized drugs under each variable.

Results: In addition to altering the aerosol characteristics, increasing the nebulizer fill volume including the addition of ipratropium bromide produced a significant (p?<?0.05) increase in the drug output. As expected, sputtering time was significantly longer at low airflows, and vice versa at higher airflows but with a significant loss of drug delivered presumably due to greater solvent evaporation at higher airflows. Airflows between 10 and 28.3?L/min and a nebulization time of approximately 10?min appear sufficient for producing aerosols within the respirable range (1–5?µm MMAD) with the nebulizer/compressor combination used. While the drug output varied significantly (p?<?0.05) among the three brands of nebulizers tested, the LC+ nebulizer appears to produce aerosols (2.7?±?0.1?µm MMAD) capable of penetrating more deeply into the lung than the other nebulizers evaluated under the current test conditions. This study did not attempt to evaluate different nebulizer/compressor combinations. Also, the cascade impaction data may not necessarily reflect aerosol deposition in the airways in vivo, which may be different depending on the health status of the patient.

Conclusion: The results demonstrated that administration of nebulized formoterol fumarate require proper selection of a delivery system/method for safe and effective therapy of the medication with and without ipratropium bromide.     

The choice of compressor effects the aerosol parameters and the delivery of tobramycin from a single model nebulizer.

Recent U.S. Phase III trials of the aerosolized delivery of tobramycin to cystic fibrosis (CF) patients demonstrated a significant improvement in pulmonary function and in sputum bacterial density. These trials used the Pari LC Plus nebulizer and DeVilbiss Pulmo-Aide compressor. This compressor is not generally available in Europe, and its power requirements do not match the European power supply. Thus alternate compressors were evaluated, using the LC Plus nebulizer, in preparation for European clinical trials. Aerosol particle size distribution, nebulization time (min), and the respirable dose of tobramycin (mg within 1-5 mu) were obtained for seven compressor models. The respirable quantity delivered by each of the European compressors (240 Volts, 50 Hz) was compared to the LC Plus and PulmoAide compressor (120 Volts, at 60 Hz). The U.S. system delivered 71.4 mg of the 300 mg instilled dose within the respirable range; using the European compressors, between 63.0 and 74.8 mg was delivered. With a 97% confidence that the delivered tobramycin was within 20% of the standard, we conclude that the SystAm 23ST, MedicAid CR50 and CR60, Pari Master and the Pari Boy compressors are equivalent to the U.S. standard; the Hercules and the SystAm 26ST compressors were not statistically equivalent to the standard. Using the LC Plus nebulizer, five European compressors delivered doses of TOBI that are similar to the doses delivered by the DeVilbiss PulmoAide compressors, and thus may be expected to produce clinical results similar to those of the U.S. trials.     

Aerosolization potential of cyclodextrins--influence of the operating conditions

The aim of this work is to characterize the aerosols obtained by jet nebulization with cyclodextrin solutions and to study the influence of operating conditions on nebulization efficiency. Two cyclodextrins, an hydroxypropyl cyclodextrin (Kleptose HP) and a polydisperse methyl beta cyclodextrin (Crysmeb), were tested with 14 nebulizers that differ geometrically. We first determined the physicochemical properties of density, viscosity, and surface tension for the cyclodextrin solutions. Nebulization efficiency was evaluated by measuring droplet size, nebulization rate, quantity of solution nebulized, and nebulization time. We studied the influence of the technological parameters of pressure and nebulizer type and the influence of the formulation on performance efficiency. The use of different nebulizers and different pressure conditions results in variable efficiency. Regardless of the type of nebulizer, an increase in pressure decreases droplet size and increases nebulization rate. The influence of the nebulizer design is considerable. The aqueous cyclodextrin solutions studied can generate aerosols in particle size ranges suitable for pulmonary deposition. Large quantities of aerosol can be nebulized in acceptable nebulization times. The cyclodextrin concentration does not modify nebulization efficiency in the range tested.     

The conventional ultrasonic nebulizer proved inefficient in nebulizing a suspension.

A study was undertaken to compare the amount of nebulized budesonide suspension and nebulized terbutaline sulphate solution inhaled by healthy adult subjects when conventional jet and ultrasonic nebulizers were used. Ten healthy subjects (5 male; age range, 16-52 years) used two conventional nebulizers: the Spira Elektro 4 jet nebulizer (Respiratory Care Center, H?meenlinna, Finland) and the Spira Ultra ultrasonic nebulizer (Respiratory Care Center) in a breath-synchronized mode with each drug. The amount of drug inhaled, the inhaled mass, was defined as the amount of drug deposited on a filter between the inspiratory port of the nebulizer and the mouthpiece. The amount of budesonide and terbutaline sulphate was determined by reversed-phase high-performance liquid chromatography. Single-dose respules were used (0.5 mg of budesonide and 5.0 mg of terbutaline sulphate), and nebulization time up to the defined gravimetric output was recorded. The inhaled mass of budesonide varied depending on the nebulizer used, whereas the inhaled mass of terbutaline was unaffected by the choice of nebulizer. The median inhaled mass of budesonide was 31.4% of the nominal dose (i.e., dose of drug in the respule per label claim) with the Spira Elektro 4 and 9.9% with the Spira Ultra, whereas the median inhaled mass of terbutaline was 50% with the Spira Elektro 4 and 52% with the Spira Ultra. It appears that a suspension is generally more difficult to nebulize than a solution and that the budesonide suspension should not be used in conventional ultrasonic nebulizers.     

In vitro characterization of nebulizer delivery of liposomal amphotericin B aerosols

Pharmaceutical aerosols have the potential to prevent pulmonary infectious diseases. Liposomal amphotericin B (LAMB, Ambisome, Astellas Pharma US, Deerfield, IL, USA) is approved as an intravenous infusion for empiric treatment of presumed fungal infections in neutropenic, febrile patients, as well as patients infected with Aspergillus, Cryptococcus, and other fungal pathogens. In this study, four different nebulizers were tested for their ability to deliver LAMB in aerodynamic droplet-size ranges relevant to lung deposition by an inertial sampling technique Mass median aerodynamic diameter (MMAD) and fine particle fraction percent <3.3 μm (FPF(3.3)) and <5.8 μm (FPF(5.8)) were determined by cascade impaction during a 2 min sampling period for each of three trials of all nebulizers. The MMADs for all nebulizers ranged from 1.72 ± 0.11 μm to 2.89 ± 0.12 μm; FPF(3.3) and FPF(5.8) were approximately 80% and 90%, respectively. Although all nebulizers appear acceptable for delivery of LAMB, the Pari LC Star and the Aeroeclipse II were considered the best in terms of delivery of aerosol efficiently and the proportion suitable for lung deposition. Additional research on pulmonary delivery and clinical tolerability is warranted.     

Compressor/nebulizers differences in the nebulization of corticosteroids. The CODE study (Corticosteroids and Devices Efficiency)

BACKGROUND: Nebulization is a common method of medical aerosol generation and it is largely used by adults and children all over the world, both for emergency treatment of acute illness and for long-term home treatment of lung diseases. The aim of this study was to determine the differences in nebulization of inhaled corticosteroids among four representative types of compressor/nebulizers. METHODS: Twelve compressor/jet nebulizers from four commercial sources were studied (three for each type): Clenny (MEDEL), Turbo Boy/LC Plus (PARI), Nebula Nuovo/MB5 (MARKOS MEFAR) and Maxaer (ARTSANA) compressor/Sidestream (Medic-Aid Ltd.) nebulizer. We compared the required time for the treatment (nebulization time), output/minutes, compressor pressures, and aerosol characteristics of inhaled corticosteroids: Beclomethasone dipropionate, Flunisolide, Fluticasone propionate and Budesonide. RESULTS: Nebulization Times showed a significant difference between nebulizer and inhaled corticosteroids for Clenny, Turbo Boy, and Maxaer. A considerable difference in the output of nebulized drugs was observed through the compressors/nebulizers. MMAD of all inhaled corticosteroids was significantly different among the four nebulizers. The percentage of particles <5 microm (respirable range) was high for all devices with beclomethasone and budesonide (> 90%), whereas with flunisolide was good only for Clenny (98.8%) and Maxaer (96.3%), and with fluticasone only for Clenny (98%), Turbo Boy (99.1%), and Maxaer (86%). Also percentage of particles <2 microm showed significant variability among the devices. CONCLUSIONS: Our results clearly demonstrate that compressor/nebulizer unit plays a key role in the effectiveness of the treatment during inhaled corticosteroid therapy, and that several differences exist in the performance of the different nebulizers studied. Therefore, the device has the same importance of the compound to reach the best clinical response in the inflammatory diseases of the lower airways.     

Aerosol characterization of nebulized intranasal glucocorticoid formulations.

Inhaled glucocorticoids (GCs) are the mainstay of long-term therapy for asthma. The lack of suitable preparations in the United States has induced clinicians to use intranasal (IN) GC formulations as "nebulizer suspensions" for off-label therapy. However, no data are available regarding aerosol production and characteristics. The aim of this study was to characterize drug outputs and aerodynamic profiles of four nebulized IN GC formulations with further analysis of flunisolide (Flu), and to test the influence of different delivery system/formulation combinations. The aerodynamic profiles and drug outputs were determined by impaction and chemical analysis. The solution output was determined by the gravimetric technique. Triamcinole acetonide (TAA), fluticasone propionate (Flut), beclomethasone dipropionate (Bec), and Flu (550, 500, 840, and 250 microg, respectively) diluted to 4 mL with saline solution were tested with the Sidestream (SID) and Aero-Tech II (AT2) nebulizers. Subsequently, Flu was tested with four additional nebulizers (Pari LC + [PARI] Acorn II, Hudson T Up-draft II, and Raindrop). All the aerosols were heterodisperse and had a particle size range optimal for peripheral airway deposition (1.85 to 3.67 microm). Flu had the highest drug output in the respirable range (22.8 and 20.3 microg/min with the AT and SID, respectively). Flu was 5-11 times more efficiently nebulized than the other formulations tested. No differences were detected in the solution outputs (0.25 to 0.3 mL/min). In subsequent testing of Flu, the PARI, AT, and SID showed the best performances. The LC+ achieved the highest drug and solution output (27.4 microg/min and 0.89 mL/min, respectively). In conclusion, Flu showed the best aerosol performance characteristics. These data do not endorse the off-label utilization of nebulized IN GC, but underscores the importance of in vitro testing before selecting any formulation/nebulizer combinations for clinical use.     

Miniaturized nebulization catheters: a new approach for delivery of defined aerosol doses to the rat lung.

A nebulization catheter technique (AeroProbe) was adapted and evaluated as a new approach for pulmonary delivery of defined aerosol doses to the rat lung. The lung distribution profile was evaluated by dosing Evans blue and Nile blue dye, respectively, to isolated and perfused rat lungs (IPL) and to the lungs of anesthetized and tracheal-intubated rats. The intratracheal aerosol dosing was synchronized with the inspiration of the lungs. Immediately after dosing, the lungs were dissected into upper- and lower trachea, bronchi, and parenchyma. The dye was then extracted from the tissue samples to determine the regional distribution and the recovery of the aerosol dose in the lungs. The droplet-size distribution and the weight of the delivered aerosol dose were analyzed with laser diffraction and gravimetric analysis respectively. The recovery of the delivered dose was high, 99 +/- 12 and 105 +/- 1%, respectively, in the in vivo administrations and IPL-experiments. The lung distribution profile after aerosol dosing to anesthetized rats was mainly tracheobronchial. Only 12 +/- 4% of the dose was recovered in the lung parenchyma. However, after aerosol dosing to the IPL, 38 +/- 11% of the dose was distributed to the lung parenchyma. At the settings used, the nebulization catheter aerosolized 1-2 microL of liquid per puff using 1-1.5 mL of air. The droplet-size distribution of the generated aerosols was broad (2-8% <3 microm; 10% <4-7 microm; 50% <10-15 microm; and 90% <20-40 microm). The nebulization catheter technique provides a complement to existing methodology for pulmonary drug delivery in small animals. With this new technique, defined aerosol doses can be delivered into the lungs of rats with no need for aerosol dosimetry.     

An in-vitro assessment of a NanoCrystal beclomethasone dipropionate colloidal dispersion via ultrasonic nebulization.

Short duration ultrasonic nebulization of a concentrated NanoCrystal colloidal dispersion of beclomethasone dipropionate demonstrated an increased respirable fraction and decreased throat deposition when evaluated in an Andersen 8-stage cascade impactor in comparison to the commercially available propellant-based product Vanceril. An aqueous-based 1.25% w/w colloidal dispersion of beclomethasone dipropionate when aerosolized via an Omron NE-U03 ultrasonic nebulizer generated a respirable drug dose from 22.6 to 39.4 micrograms per 2 s actuation period, compared to 12.8 micrograms for a single actuation of Vanceril. When viewed as a percentage of the emitted dose (through the actuator or mouthpiece), the respirable fraction ranged from 56 to 72% for the nanocrystalline formulation versus 36% for the propellant system. In addition, the throat deposition as seen in the induction port was 9-10% of the emitted dose for the novel suspension, as compared to 53% for the commercial product. Thus, when used with the device outlined herein, a nanocrystalline colloidal suspension of beclomethasone dipropionate affords greater potential drug delivery to the conductive airways of the lung in both quantity and as a percent of emitted dose. Additionally, lower potential throat deposition values were observed which may retard the development of undesirable side effects, such as candidiasis, when compared to a propellant based delivery system. Lastly, the ability to atomize aqueous-based nanocrystalline colloidal dispersions represents an environmentally sound alternative to the current chlorofluorocarbon (CFC)-based products and may avoid the technical difficulties of reformulating with chlorine-free propellants.     

Spray Dried Powders and Powder Blends of Recombinant Human Deoxyribonuclease (rhDNase) for Aerosol Delivery

Purpose. We have used rhDNase to investigate the feasibility of developing a dry protein powder aerosol for inhalation delivery. Methods. Powders of rhDNase alone and with sodium chloride were prepared by spray drying. Powder blends were obtained by mixing (tumbling and sieving) pure rhDNase powder with 'carrier' materials (lactose, mannitol or sodium chloride). The weight percent of drug in the blends was between 5 and 70%. The particle size distributions and crystallinity of the spray dried powders were obtained by laser diffraction and X-ray powder diffraction, respectively. Particle morphology was examined by scanning electron microscopy. The ability of the powders and powder blends to be dispersed into respirable aerosols was measured using a Rotahaler connected to a multistage liquid impinger operating at 60 L/min. Results. Pure rhDNase powder was quite cohesive with a fine particle fraction (FPF or 'respirable fraction': % wt. of particles < 7 m in the aerosol cloud) of about 20%. When particles also contained NaCl, the powders were dispersed better to form aerosols. A linear relationship was observed between the NaCl content and FPF for a similar primary size (~3 m volume median diameter) of particles. The particle morphology of these powders varied systematically with the salt content. For the blends, SEM revealed a monolayer-like adhesion of the fine drug particles to the carriers at drug contents 50 % wt. An overall 2-fold increase in FPF of rhDNase in the aerosol cloud was obtained for all the blends compared to the pure drug aerosols. Conclusions. The aerosol properties of spray dried rhDNase powders can be controlled by incorporation of a suitable excipient, such as NaCl, and its relative proportion. Coarse carriers can also enhance the performance of rhDNase dry powder aerosols.     

Aerosols and anti-infectious agents.

Anti-infectious agents such as pentamidine, antibiotics (mainly colistine and aminoglycosides), and amphotericin B can be administered by aerosol. Apart from pentamidine and Tobi, this route of administration is not officially approved and it constitutes an empirical approach, which has benefited from recent research summarized hereafter. The most fundamental question is related to the potentially deleterious effects of nebulization processes, especially ultrasound, on the anti-infectious properties of the drugs. Colimycin, which was chosen as a reference because its polypeptide structure makes it unstable a priori, proved to be resistant to high frequency ultrasound, which is encouraging for other molecules such as aminoglycosides or betalactamins. The nebulizer characteristics also have to be taken into account. An aerosol can be produced from an amphotericin B suspension and from colistine using both an ultrasonic nebulizer and a jet nebulizer. Differentiating between good and bad nebulizers is not dependent upon the physical process involved to nebulize the drug, but on the intrinsic characteristics of the device and its performance with a known drug. The inhaled mass of an aerosol in the respirable range must be high and dosimetric nebulizers represent significant progress. Finally, administration of anti-infectious aerosols requires a new pharmacological approach to monitor treatment, and urinary assays are promising for this purpose.