Comparative analysis of methods to measure aerosols generated by a vibrating mesh nebulizer.

Different approaches have been employed for in vitro assessment of the aerosol particle size generated by inhalation devices. In this study, aerosols from the Omron MicroAir vibrating mesh (VM) nebulizer were measured by cascade impaction (CI) using the MSP Next Generation Pharmaceutical Impactor (NGI), the ThermoAndersen Cascade Impactor (ACI), and by time-of-flight (TOF) analysis with the TSI 3321 Aerodynamic Particle Sizer Spectrometer (APS). The VM nebulizer was evaluated with sodium fluoride (NaF; 2.5%) and with generic albuterol (0.083%). Aerosol particle size (MMAD), respirable fractions (RF < 5 microm), and fine particle fractions (FPF < 3.3 microm) were determined with each method at room temperature (RT) and 4 degrees C using 50% average relative humidity. By NGI at either RT or 4 degrees C, aerosol particle sizes were similar for both NaF and albuterol (4.3-4.5 microm MMAD) with 55-61% RF and 27-43% FPF. With ACI, the distribution of particles at RT was similar except at the extremes of the dispersion and the MMAD was smaller (3.3 microm MMAD; p = 0.03). At 4 degrees C, particle sizes determined by ACI results were similar to the NGI (MMAD 4.1 microm; p > 0.05). TOF analysis by APS with albuterol gave significantly larger calculated MMAD (cMMAD) than either CI method (7.2 microm; p < 0.001). TOF measurements of nebulized albuterol at RT and 4 degrees C were equivalent. In summary, the results of VM nebulized NaF and albuterol were more consistent and generally equivalent when determined by NGI (at RT and 4 degrees C) and ACI analysis (at 4 degrees C). In contrast, aerosol particle sizes measured by TOF in the APS at both RT and 4 degrees C were larger than results obtained by CI. Differences in aerosol particle distribution obtained by different analysis methods should be considered while evaluating the in vitro performance of VM nebulizers.     

In vitro determination of the optimal particle size for nebulized aerosol delivery to infants.

We investigated the in vitro influence of breathing patterns on lung dose (LD) and particle size distribution in an infant upper airway cast model in order to determine the optimal particle size for nebulized aerosol delivery to infants. Budesol (nebulizer solution of budesonide) delivery from a perforated vibrating membrane nebulizer (eFlow Baby functional prototype) through an upper airway cast of a nine month old infant (SAINT-model) was measured at a fixed respiratory rate (RR) of 30 breaths per minute (bpm) and a tidal volume (Vt) of 50, 100, and 200 mL, respectively, and at a fixed Vt of 100 mL and a RR of 30, 60, and 78 bpm, respectively. LD expressed as a percentage of the nominal dose (ND; range, 5.8-30.3%) decreased with increasing Vt (p < 0.001) and with increasing RR (p < 0.001). Median mass aerodynamic diameter (MMAD) after passage (range, 2.4-3.4 microm) through the upper airway cast showed a negative correlation with increasing Vt (p < 0.001) and with increasing RR (p = 0.015). Particles available as LD for all simulated breathing pattern showed a particle size distribution with a MMAD of 2.4 microm and a geometric standard deviation (GSD) of 1.56. From our in vitro study, we conclude that the optimal particle size for nebulized aerosols for inhalation therapy for infants should have a MMAD of <2.4 microm.     

High-Output Generation of Aerosols with Narrow Size Distributions

Abstract

Two aerosol generators–a small particle generator (SPG) and a large particle generator (LPG)–were designed and fabricated to produce water-soluble particles with high mass output and narrow size distributions. The mass median aerodynamic diameter (MMAD) of solid particles produced could be varied by changing operation conditions and using different concentrations of sodium chloride (NaCl) solutions. The aerosol generation rate varied from about 0.2 to 24 mg/min depending upon the particle size produced as the geometric standard deviation (GSD) was maintained below 1.5. The SPG employed a Collison-type nebulizer with multiple nozzles and a solid-plate impactor, which removes generating droplets larger than the cutpoint diameter for the production of submicrometer aerosols with GSD < 1.5. Different combinations of nebulization pressure/cutpoint diameter were selected to produce solid particles with MMAD in the range of 0.13–1.0 μm. The LPG was consisted of a Delavan simplex nozzle installed at the bottom of the generation chamber (about 190 cm in height and 15 cm in diameter) and an improved virtual impactor located at the top of the generation chamber. Gravity was used to remove large droplets and the improved virtual impactor was employed to remove droplets less than the cutpoint diameter. Two sets of acceleration nozzle and collection probe were used to vary the impactor cut size. The size-selective droplets were then evaporated to form solid particles with the MMAD nominally varying from 1 to 10 μm and GSD < 1.5.     

Cascade impactor data and the lognormal distribution: nonlinear regression for a better fit.

At present, cascade impactors are the instruments of choice for measuring the particle size distribution of aerosol present in the complex discharge from pharmaceutical inhalers. The distribution of drug captured in the cascade impactor may be most usefully represented by the lognormal distribution. Only two parameters must be extracted from the analysis of cascade impactor data in order to describe the distribution. These two parameters are the mass median aerodynamic diameter (MMAD) and the geometric standard deviation (GSD). A cumulative version of the lognormal curve or more frequently, a linearized version of the cumulative curve called a "log probability plot," is used as a surrogate for the lognormal curve. The probability plot has great appeal since a lognormal distribution yields a straight line on log probability paper. One may easily determine the apparent MMAD and GSD from this linear plot. However, when one plots a lognormal curve, using the MMAD and GSD derived from a log probability plot, over a histogram constructed from cascade impactor data, an obvious mismatch is frequently seen. In order to derive parameters that more truly reflect the impactor data, a computer program, which uses nonlinear regression to derive an MMAD and GSD for the lognormal curve, has been written. It is presented here.     

Levalbuterol Nebulizer Solution: Is It Worth Five Times the Cost of Albuterol?

Albuterol is a 50:50 mixture of R-albuterol, the active enantiomer, and S-albuterol, which appears to be inactive in humans. The Food and Drug Administration recently approved levalbuterol, the pure R-isomer, as a preservative-free nebulizer solution. Published studies indicate that it is neither safer nor more effective than an equimolar dose of racemic albuterol (levalbuterol 1.25 mg = albuterol 2.5 mg). However, these studies were conducted in patients with stable asthma (at the top of the dose-response curve), whereas a nebulized bronchodilator most likely would be used by patients with an acute exacerbation. Because such patients, in the hospital setting, often require higher doses of albuterol, the manufacturer's recommended dose of levalbuterol is likely to be too low for rescue therapy. Levalbuterol may cost as much as 5 times more than racemic albuterol, depending on purchase method. We conclude that levalbuterol offers no advantage over albuterol but is likely to be more costly.     

Experimental pulmonary delivery of cyclosporin A by liposome aerosol

The utilization of CsA–liposome for aerosol delivery by jet nebulizers has potential advantages for clinical development including: aqueous compatibility, sustained pulmonary release to maintain therapeutic drug levels and facilitated delivery to alveolar macrophages and pulmonary lymphocytes. Inhalation of cyclosporin A (CsA)–dilauroylphosphatidylcholine (DLPC) liposome aerosols will theoretically result in localized and sustained delivery of therapeutic CsA concentrations within the lung as an alternative to local immunotherapy for pulmonary diseases. In the lung, targeted delivery of therapeutic CsA concentrations would require lower dosages than via conventional intravenous or oral routes of administration. Potential benefits from targeted lung delivery could include reduced systemic toxicity and prolonged immunosuppressive activity. Aerosol delivery systems have been developed to deposit drugs directly onto pulmonary surfaces at the sites of disease within the lung. A novel HPLC method for tissue analysis of CsA–liposomes is developed and utilized with a solid-phase extraction method to measure CsA recovered from Balb/c mouse lung tissues. A concentrated formulation containing 5 mg CsA–37.5 mg DLPC/ml was nebulized with an Aerotech II nebulizer generating an aerosol particle size distribution (mass median aerodynamic diameter (MMAD)) of 1.7 μm and geometric standard deviation (GSD) of 2.0. After a 15-min aerosol exposure, little of no CsA was detected in the blood, liver, kidney or spleen. The lung contained the highest organ CsA levels with high immunosuppressive activity demonstrating effective pulmonary targeting of the CsA–DLPC liposome aerosol. The results of this system will be utilized as the experimental basis for future pharmacokinetic, toxicological, immunosuppression and other biological studies.     

Loading Effect on Particle Size Measurements by Inertial Sampling of Albuterol Metered Dose Inhalers

Purpose. The purpose of this study is to investigate the albuterol loading effect on particle size measurements by studying the effect of the amount of albuterol delivered, the number of puffs used, and the sampling techniques used in particle size measurement. Methods. Particle size distribution profiles for different albuterol loadings were evaluated using an 8-stage cascade impactor and a sensitive HPLC electrochemical assay method. A commercial albuterol MDI (Proventil^R) and other specially prepared albuterol MDIs were used in the study. Results. As the amount of albuterol was increased, either by increasing the number of puffs or the amount delivered per puff, the measured MMAD increased. This increase was more prominent in some formulations (Proventil^R) than others. Further, albuterol particles previously deposited on the valve and/or actuator didn't play a role in the observed multi-puff/loading effect. Conclusions. The collection of the least amount of aerosol in a cascade impactor provides a better estimate of MMAD, as it minimizes modifications of the collection surfaces.     

Aerosolized protein delivery in asthma: gamma camera analysis of regional deposition and perfusion.

Bioavailability of an aerosolized anti-inflammatory protein, soluble interleukin-4 receptor (IL-4R), was measured in patients with asthma using two different aerosol delivery systems, a prototype aerosol delivery system (AERx tethered model, Aradigm, Hayward, CA) and PARI LC STAR nebulizer (Pari, Richmond, VA). Regional distribution of the drug in the respiratory tract obtained by planar imaging using gamma camera scintigraphy was utilized to explain the differences in bioavailability. The drug, an experimental protein being developed for asthma, was mixed with radiolabel 99mTechnetium diethylene triaminepentaacetic acid (99mTc-DTPA). Aerosols were characterized in vitro using cascade impaction (mass median aerodynamic diameter [MMAD] and geometric standard deviation [GSD]); the AERx MMAD 2.0 microm (GSD 1.35), the PARI 3.5 microm (GSD 2.5). Four patients with asthma requiring maintenance aerosolized steroids were studied. First, regional volume was determined utilizing equilibrium 133Xe scanning. Then, after a brief period of instruction, patients inhaled four breaths of protein using AERx (0.45 mg in total) followed 1 week later by inhalation via PARI (3.0 mg nebulized until dry). Each deposition image was followed by a measurement of regional perfusion using injected 99mTc albumin macroaggregates. Deposition of 99mTc-DTPA in the subjects was determined by mass balance. Regional analysis was performed using computerized regions of interest. The regional distribution of deposited drug was normalized for regional volume and perfusion. Following each single inhalation, serial blood samples were drawn over a 7-day period to determine area under the curve (AUC) of protein concentration in the blood. Median AUC(AERx)/AUC(PARI) was 7.66/1, based on the amount of drug placed in each device, indicating that AERx was 7.66 times more efficient than PARI. When normalized for total lung deposition (AUC per mg deposited) the ratio decreased to 2.44, indicating that efficiencies of the drug delivery system and deposition were major factors. When normalized for sC/P and (pU/L)xe ratios (central to peripheral and upper to lower ratios are parameters of regional distribution of deposited particles and regional per- fusion ['p']), AUC(AER)x/AUC(PARI) further decreased to 1.35, demonstrating that peripheral sites of deposition with the AERx affected the final blood concentration of the drug. We conclude that inhaled bioavailability of aerosolized protein, as expressed by AUC, is a quantifiable function of lung dose and regional deposition as defined by planar scintigraphy.     

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.     

Influence of Impactor Operating Flow Rate on Particle Size Distribution of Four Jet Nebulizers

When a nebulizer is evaluated by the Andersen Cascade Impactor (ACI), the flow rate is generally maintained at 28.3 L/min, as recommended by the manufacturer. However, the nebulizer flow rate that a patient inhales is only around 18 L/min. Because the drive flow of a nebulizer is approximately 6–8 L/min, the nebulized drug is mixed with outside air when delivered. Evaluating impactor performance at the 28.3 L/min flow rate is less than ideal because an additional 10 L/min of outside air is mixed with the drug, thereby affecting the drug size distribution and dose before inhalation and deposition in the human lung. In this study we operated the ACI at an 18.0 L/min flow rate to test whether the effect of the changing ambient humidity was being exaggerated by the 28.3 L/min flow rate. The study was carried out at three different relative humidity levels and two different impactor flow rates with four commercially available nebulizers. The mass median aerodynamic diameter (MMAD) and the geometric standard deviation (GSD) of the droplets were found to increase when the impactor was operated at a flow rate of 18 L/min compared to that of 28.3 L/min. The higher MMAD and GSD could cause the patient to inhale less of the drug than expected if the nebulizer was evaluated by the ACI at the operating flow rate of 28.3 L/min.     

Influence of impactor operating flow rate on particle size distribution of four jet nebulizers

When a nebulizer is evaluated by the Andersen Cascade Impactor (ACI), the flow rate is generally maintained at 28.3 L/min, as recommended by the manufacturer. However, the nebulizer flow rate that a patient inhales is only around 18 L/min. Because the drive flow of a nebulizer is approximately 6-8 L/min, the nebulized drug is mixed with outside air when delivered. Evaluating impactor performance at the 28.3 L/min flow rate is less than ideal because an additional 10 L/min of outside air is mixed with the drug, thereby affecting the drug size distribution and dose before inhalation and deposition in the human lung. In this study we operated the ACI at an 18.0 L/min flow rate to test whether the effect of the changing ambient humidity was being exaggerated by the 28.3 L/min flow rate. The study was carried out at three different relative humidity levels and two different impactor flow rates with four commercially available nebulizers. The mass median aerodynamic diameter (MMAD) and the geometric standard deviation (GSD) of the droplets were found to increase when the impactor was operated at a flow rate of 18 L/min compared to that of 28.3 L/min. The higher MMAD and GSD could cause the patient to inhale less of the drug than expected if the nebulizer was evaluated by the ACI at the operating flow rate of 28.3 L/min.     

Effect of helium-oxygen on delivery of albuterol in a pediatric, volume-cycled, ventilated lung model

Pulmonary delivery of inhaled bronchodilators in mechanically ventilated patients is inefficient whether administered by metered-dose inhaler (MDI) or small-volume nebulizer. One of the factors that causes inefficient aerosol delivery is turbulent gas. Heliox (He:O2) is a blend of helium and oxygen that is less dense than air, making turbulent flow less likely. We assessed the effect of 70% He:O2 on albuterol delivery in a mechanically ventilated pediatric lung model. Albuterol was administered by MDI with spacer, collected on a filter proximal to a test lung, and measured by high-performance liquid chromatography. Mean amount and percentage albuterol delivered were significantly (p<0.05) greater for 70% He:O2 (395+/-29 microg, 20+/-3.2%) than for 70% nitrogen:30% oxygen (241+/-29 microg,12+/-1.7%). Thus 70% He:O2 can increase the amount of albuterol delivered at the end of the endotracheal tube, suggesting a potential role for it in the care of critically ill ventilated patients.     

Changes induced by sodium cromoglycate in brain catecholamine turnover in morphine dependent and abstinent mice

The effects of sodium cromoglycate (CRO) were studied in relation to the metabolism of brain catecholamines: dopamine (DA) and noradrenaline (NA), and their metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 4-hydroxy-3-methoxyphenylethyleneglycol (MHPG). CRO was injected SC in control mice, morphine-tolerant mice (tolerance was induced by SC implantation of a 75 mg morphine pellet; CRO was administered on day 4 of addiction) and 30 min before abstinence (withdrawal was induced by SC injection of naloxone (1 mg/kg) on day 4 of addiction). Brain catecholamines and their metabolites were measured using high performance liquid chromatography coupled with electrochemical detection (HPLC-ECD), for DA, NA, DOPAC and HVA, and coupled with fluorescence detection for MHPG. The ratios of DOPAC + HVA/DA and MHPG/NA were kept as an index of DA and NA turnovers, respectively. CRO administered 30 min before naloxone-precipitated withdrawal diminished significantly NA levels in frontal cortex. CRO increased DA turnover in striatum and frontal cortex in naive animals and significantly diminished DA levels in frontal cortex and DOPAC levels in frontal cortex and midbrain in morphine-dependent mice. These findings are discussed in relation to the protective effects of CRO on opiate withdrawal and the effects of CRO on locomotor activity.This work was supported by a grant from the Fondo de Investigaciones Sanitarias de la Seguridad Social (FIS, programme no. 0166/93).     

Nebulization of Active Pharmaceutical Ingredients with the eFlow®rapid: Impact of Formulation Variables on Aerodynamic Characteristics

Nebulization of active pharmaceutical ingredient (API) solutions is a well-established means to achieve pulmonary drug deposition. The current study identified the impact of formulation variables on the aerosolization performance of the eFlow®rapid with special respect to optimized lung application. API formulations (including excipient-supplemented samples) were investigated for physicochemical properties, then nebulized using vibrating-mesh technology. The generated aerosol clouds were analyzed by laser diffraction. Aerosol deposition characteristics in the human respiratory tract were estimated using an algebraic model. Remarkable effects on aerosolization performance [i.e., mass median aerodynamic diameter (MMAD)] of API solutions were obtained when the sample conductivity (by API concentration and type, sodium chloride addition) and dynamic viscosity (by application of sucrose and poly(ethylene glycol) 200) were elevated. A similar influence was observed for a decline in surface tension (by ethanol addition). Thus, a defined adjustment of formulation parameters allowed for a decrease of the MMAD from ∼8.0 μm to values as small as ∼3.5 μm. Consequently, the pattern and efficiency of aerosol deposition in the human respiratory tract were improved. In conclusion, identification of physicochemical variables and their way of influencing vibrating-mesh nebulization has been provided to deliver a platform for tailoring aerosol characteristics and thus, advancing pulmonary therapy. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2585–2589, 2014     

Performance of a portable whole-body mouse exposure system

A mobile whole-body exposure system was developed for exposing mice to concentrated ambient particulate matter smaller than 2.5 microm in mass median aerodynamic diameter (MMAD). Each 20-L exposure cage was designed to hold 9 mice within individual compartments. This allowed for transport and subsequent exposure. Airflow mixing and the potential for stagnant areas within the compartments were modeled using computational fluid dynamic modeling (CFD). CFD analysis showed no stagnant areas and good mixing throughout the exposure cage. The actual performance of the exposure system was determined for 0.5 to 2.0 microm diameter aerosols by measuring (1) uniformity of aerosol distribution and (2) particle deposition in the tracheobronchial and pulmonary regions of mice exposed in the system. A 0.6-microm MMAD (GSD=2.0) cigarette smoke aerosol was used to experimentally measure the uniformity of aerosol distribution to the nine individual compartments. The average data from three runs showed no statistically significant difference among individual compartments. Particle deposition efficiency in adult male BALB/c mice was measured after exposure (30 min) in the system using monodisperse fluorescent polystyrene latex particles (0.5, 1, and 2 microm aerodynamic diameter). The measured deposition efficiency in this mobile exposure system for the combined tracheobronchial and pulmonary regions of the adult male BALBc mice was 21% for 0.5 microm, 11% for 1.0 microm, and 6.5% for 2.0 microm particles. These deposition efficiencies are similar to those reported for mice exposed in a nose-only exposure system, which indicates that particle losses to animal fur and exposure system surfaces were acceptable.     

Performance of a Portable Whole-Body Mouse Exposure System

A mobile whole-body exposure system was developed for exposing mice to concentrated ambient particulate matter smaller than 2.5 μm in mass median aerodynamic diameter (MMAD). Each 20-L exposure cage was designed to hold 9 mice within individual compartments. This allowed for transport and subsequent exposure. Airflow mixing and the potential for stagnant areas within the compartments were modeled using computational fluid dynamic modeling (CFD). CFD analysis showed no stagnant areas and good mixing throughout the exposure cage. The actual performance of the exposure system was determined for 0.5 to 2.0 μm diameter aerosols by measuring (1) uniformity of aerosol distribution and (2) particle deposition in the tracheobronchial and pulmonary regions of mice exposed in the system. A 0.6-μm MMAD (GSD = 2.0) cigarette smoke aerosol was used to experimentally measure the uniformity of aerosol distribution to the nine individual compartments. The average data from three runs showed no statistically significant difference among individual compartments. Particle deposition efficiency in adult male BALB/c mice was measured after exposure (30 min) in the system using monodisperse fluorescent polystyrene latex particles (0.5, 1, and 2 μm aerodynamic diameter). The measured deposition efficiency in this mobile exposure system for the combined tracheobronchial and pulmonary regions of the adult male BALBc mice was 21% for 0.5 μm, 11% for 1.0 μm, and 6.5% for 2.0 μm particles. These deposition efficiencies are similar to those reported for mice exposed in a nose-only exposure system, which indicates that particle losses to animal fur and exposure system surfaces were acceptable.     

Selecting an accessory device with a metered-dose inhaler: variable influence of accessory devices on fine particle dose, throat deposition, and drug delivery with asynchronous actuation from a metered-dose inhaler.

Accessory devices reduce common problems with metered-dose inhalers (MDIs), namely high oropharyngeal deposition of aerosol and incoordination between actuation and inhalation by the patient. The objective of this study was to systematically compare the performance of various accessory devices in vitro. MDIs were tested alone or in combination with four spacers (Toilet paper roll, Ellipse, Optihaler, Myst Assist) and five holding chambers (Aerochamber, Optichamber, Aerosol Cloud Enhancer, Medispacer, and Inspirease). An Anderson cascade impactor was used to measure aerosol mass median aerodynamic diameter (MMAD) and fine particle dose (MMAD < 4.7 microm). In separate experiments, the influence of asynchronous MDI actuation on drug delivery was determined with a simulated spontaneous breathing model. Compared with the MDI alone, all of the accessory devices reduced aerosol MMAD and increased lung-throat ratio (fine particle dose/throat impaction; p < 0.05 for both parameters). The fine particle dose of albuterol was 40% higher with the Ellipse (p < 0.01), was equivalent with the Toilet Paper Roll, Aerochamber, Optichamber, and Medispacer, and was 33-56% lower with the Optihaler, Myst Assist, Aerosol Cloud Enhancer, and Inspirease (p < 0.03). MDI actuation in synchrony with inspiration produced highest drug delivery; when MDI actuation occurred 1-sec before inspiration or during exhalation, decrease in drug delivery with holding chambers (10-40% reduction) was less than that with spacers (40-90% reduction). Accessory device selection is complicated by variability in performance between devices, and in the performance of each device in different clinical settings. In vitro characterization of a MDI and accessory device could guide appropriate device selection in various clinical settings.     

Evaluation of a new Aerodynamic Particle Sizer Spectrometer for size distribution measurements of solution metered dose inhalers.

The ability of the Model 3320 and newer Model 3321 Aerodynamic Particle Sizer Spectrometer (APS) to make accurate mass-weighted size distribution measurements of solution metered dose inhalers (MDIs) was evaluated. Measurements of experimental HFA-134a beclomethasone dipropionate MDIs were made with both the APS 3320 and APS 3321 and compared to the Andersen Cascade Impactor (ACI). The mass-weighted size distribution measurements from the ACI and APS 3321 agreed well but were very different than the APS 3320 measurements. Evaluation of the APS 3320 size distribution measurements indicated that the presence of a few erroneous particle measurements caused a gross overestimation of the mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD). When a previously described technique was used to eliminate erroneous particle size measurements from the size distribution calculation, the MMAD and GSD from the APS 3320 agreed well with those from the ACI and APS 3321. The GSD from the APS 3321 and the APS 3320 after a mask was applied were slightly larger than from the ACI. It is believed that both APS instruments slightly underestimate the GSD while the ACI slightly overestimates the GSD. Further experiments were conducted using the APS 3321 to examine the influence of drug concentration and cosolvent level on the size distribution of solution formulation MDIs. The MMAD was shown experimentally and theoretically to be proportional to drug concentration to the one-third power. Cosolvent concentration had minimal influence on MMAD over the range examined. The measurements reported in this paper demonstrate that it is possible to obtain accurate mass-weighted size distribution measurements with the APS 3320 and APS 3321. These instruments allow for accurate size distribution measurements to be made in minutes as opposed to the hours required to conduct and analyze size distribution measurements from cascade impactors.     

The study of in vitro-in vivo correlation: pharmacokinetics and pharmacodynamics of albuterol dry powder inhalers

The pharmacokinetics and pharmacodynamics of albuterol were studied following inhalation of three different in-house dry powder formulations in healthy volunteers and in asthmatics. Albuterol in plasma was measured using liquid chromatography-mass spectrometry (LC-MS). The plasma concentration time profiles were fitted to a two-compartment model with first-order kinetics. Oral absorption of swallowed albuterol was eliminated by oral dosing of 560 mg activated charcoal 1 h prior to albuterol aerosol administration. The peak concentration was reached within 15-20 min. Mean peak concentrations in healthy volunteers (six males and six females) were 1.74 +/- 0.34, 2.01 +/- 0.35, and 2.59 +/- 0.27 ng/mL following inhalation of formulations with fine particle doses (FPDs) of 100, 120, and 160 microg of albuterol, respectively. The corresponding peak plasma concentrations of 1.23 +/- 0.29, 1.37 +/- 0.13, and 1.53 +/- 0.11 ng/mL were obtained when asthmatics (six males and six females) were dosed with the same three formulations. The FPD of each formulation correlated well with the area under the curve of plasma concentration-time (AUC(0-8)) profile. Plasma potassium did not show any significant change over a period of 8 h. The forced vital capacity (FVC), the force expiratory volume in 1 s (FEV(1)), and mid expiratory flow (FEF(25-75)) did not correlate with FPD for the three different formulations.     

Determination of the bioavailability of gentamicin to the lungs following inhalation from two jet nebulizers

AIMS: To determine the bioavailability of gentamicin to the lung following inhalation from two jet nebulizers. METHODS: Serial urine samples were obtained from 10 volunteers after a 80 mg dose given orally, nebulized from a Pari LC + (PARI) and MicroNeb III (MN) devices, or after a 40 mg intravenous dose. In vitro aerodynamic characteristics of the nebulized doses were also determined. RESULTS: The mean (SD) absolute gentamicin lung bioavailalibility following delivery by PARI and MN devices was 1.4 (0.4) and 1.7 (0.5) %. The mass median aerodynamic diameter (MMAD) of the drug particles from the PARI and MN systems was 8.6 (0.6) and 6.7 (0.5) microm and the corresponding fine particle doses (FPD) were 10.2 (2.8) and 11.7 (1.5) mg. CONCLUSIONS: The MMAD and FPD data reflect the poor lung deposition of gentamicin identified by urinary excretion.