Effect of heliox on albuterol delivery by metered-dose inhaler in pediatric in vitro models of mechanical ventilation

STUDY OBJECTIVE: To determine the effect of varying concentrations of heliox, a mixture of helium and oxygen, on albuterol delivery administered by metered-dose inhaler (MDI) in pediatric mechanically ventilated models. DESIGN: Prospective in vitro laboratory study. SETTING: University-affiliated research laboratory. MODELS: The lungs of a 10-kg infant and 30-kg child receiving humidified pressure-regulated volume-controlled ventilation were simulated. The infant settings were an endotracheal tube (ETT) of 4.0 mm, tidal volume of 150 ml, positive end-expiratory pressure of 2 cm H(2)O, rate of 20 breaths/minute, inspiratory time of 0.7 second; the child settings were an ETT of 6.0 mm, tidal volume of 450 ml, positive end-expiratory pressure of 2 cm H(2)O, rate of 16 breaths/minute, and inspiratory time of 0.8 second. MEASUREMENTS AND MAIN RESULTS: Ten albuterol MDI canisters with chlorofluorocarbon propellants were each actuated once sequentially (total dose 1000 mug) with a commercially available aerosol holding chamber. Albuterol was collected onto a filter proximal to a lung simulator. The filter was rinsed, and concentrations were determined by high-performance liquid chromatography. In the infant model, heliox mixtures of 70:30, 60:40, and 50:50 were compared with nitrogen:oxygen (N(2):O(2)) mixtures in the same ratios. The effect of the 70:30 mixtures was also explored in a child model. Each gas mixture was tested 5 times. At all three ratios, albuterol delivery to the end of the ETT was improved with heliox compared with N(2):O(2) (approximately 7% vs 3-4%, p<0.0001, one-way analysis of variance [ANOVA] with a Bonferroni correction for multiple comparisons). No significant difference was noted in mean percentage albuterol delivery among the varying ratios of heliox studied. By two-way ANOVA, significantly greater albuterol delivery was noted with 70:30 heliox compared with 70:30 N(2):O(2) (7-8% vs 3%, p<0.0001), with no significant difference between the infant and child model (p=0.21). The gas mixture, model, and interaction of the two explained 88% of the variability in mean percentage albuterol delivery. CONCLUSION: Heliox increased albuterol delivery administered by MDI to the end of the ETT in these in vitro pediatric models of mechanical ventilation. Further studies are needed to determine if the improved albuterol delivery with heliox enhances clinical response in infants and children needing mechanical ventilation.     

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.     

Relative lung and total systemic bioavailability following inhalation from a metered dose inhaler compared with a metered dose inhaler attached to a large volume plastic spacer and a jet nebuliser

OBJECTIVE: To compare the lung and systemic delivery of salbutamol following inhalation from a metered dose inhaler (MDI), a MDI attached to a spacer (MDI+SP) and a nebuliser (NEB) using a urinary pharmacokinetic method. METHOD: Twelve healthy subjects each provided urine samples at 0, 30 min and pooled up to 24 h after the start of 5 x 100 microg salbutamol inhaled from MDI and MDI + SP and after 2.5 mg was delivered by NEB. Following nebulisation, the amount of salbutamol trapped on an exhalation filter together with that remaining in the apparatus was determined. The amount left in the spacer and that leaving the MDI mouthpiece was also determined. Thus, for all the methods, the amount available for inhalation from each study dose was determined. RESULTS: The mean (+/- SD) 30-min urinary excretion amounts of salbutamol for MDI, MDI+SP and NEB were 12.6+/-3.5, 27.1+/-6.0 and 16.1+/-4.6 microg, respectively. The mean ratios (90% confidence intervals) for MDI+SP compared with MDI and NEB were 230.2 (186.7, 273.8) and 183.0 (146.4, 219.7) (both P values<0.001), respectively, while that between MDI and NEB was 134 (110.4, 159.1) (P < 0.05). The mean (+/-SD) 24-h urinary excretion values for salbutamol and its metabolite were 287.0+/-46.5, 198.1+/-34.7 and 253.4+/-138.3 microg, respectively. Following inhalation a mean of 202.9+/-51.5 microg was left in the spacer. Similarly, after nebulisation 1387.7+/-88.9 microg was left in the nebuliser chamber, 26.3+/-8.0 microg in the mouthpiece and 553.8+/-68.5 microg exhaled. The mean emitted dose from the MDI was 88.4+/-6.1 microg per actuation. When normalised for the amounts available for inhalation, the mean amounts of salbutamol excreted in the urine during the first 30 min were 2.86+/-0.78, 9.15+/-1.69 and 3.06+/-0.70% following MDI, MDI + SP and NEB, respectively. CONCLUSION: Five 100-microg doses inhaled from a metered dose inhaler attached to a spacer delivered more to the lungs and less to the systemic circulation than either the same doses from a metered dose inhaler used alone or five times the dose given via a jet nebuliser. Spacers should be routinely used instead of nebulisers to manage patients unless they are short of breath.     

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.     

Effect of inhalation flow rate on the dosing characteristics of dry powder inhaler (DPI) and metered dose inhaler (MDI) products.

Both the dose delivered from the device and the particle size of the medication are important parameters for inhalation products because they influence the amount of drug that is delivered to the patient's lung. The inspiratory flow rate may vary from dose to dose in a given patient and between patients. The Marple-Miller Cascade Impactor, a new multistage inertial impactor that operates at two flow rates (30 and 60 liters/min) with comparable particle size cut-offs, provides a means to study the effect of inhalation flow rate on the particle size distributions of inhalation products. The medication delivery, mass median aerodynamic diameter (MMAD), and fine particle mass were determined, in a randomized fashion, for albuterol, beclomethasone, budesonide, and terbutaline in both metered dose inhaler (MDI) and dry powder inhaler (DPI) products as a function of flow rate. In all cases, independent of drug or device used, the MDI products had a more reproducible respirable dose than the breath-actuated DPI products tested as a function of inhalation flow rate.     

Particle Size and Charge Distribution Analysis of Pharmaceutical Aerosols Generated by Inhalers

Aerosol particles generated by inhalers for respiratory drug delivery acquire electrostatic charge during the dispersion process. The electrostatic charge distribution of the particles can affect the efficiency of drug delivery by influencing both the transport and deposition of inhaled particles in the human lung. To analyze the electrostatic charge acquired by the aerosol particles, two sets of metered-dose inhaler (MDI) and dry powder inhaler (DPI) devices were investigated. Both the particle size and charge distributions were measured simultaneously by using an electrical single-particle aerodynamic relaxation time (E-SPART) analyzer. The analyzer was calibrated with particles of known size, which were generated by a vibrating orifice aerosol generator (TSI Inc.) and charge using the Faraday cup method. The charge distributions of the pharmaceutical aerosols from both the DPI and MDI devices were bipolar in nature. Although the net charge-to-mass ratio was less than 0.2 μC/g, the individual particles were charged with a relatively high charge: ?2 to + 2 μC/g. The count mean aerodynamic diameter of the aerosols generated from these devices was 3–5 μm.     

Automatic replacement of albuterol nebulizer therapy by metered-dose inhaler and valved holding chamber.

PURPOSE: Evidence supporting the delivery of bronchodilators with a metered-dose inhaler and a valved holding chamber (MDI+VHC) in place of a small-volume nebulizer (SVN) is discussed, and the steps taken to accomplish such a conversion program at one institution are described. SUMMARY: Double-blind, randomized studies in patients with acute exacerbations of asthma have demonstrated that higher doses of albuterol delivered by MDI+VHC (4-10 puffs per dose) are as effective as 2.5 mg of albuterol sulfate delivered by SVN. Three double-blind studies support the conclusion that the two methods are equivalent with respect to both efficacy and adverse effects in patients with chronic obstructive pulmonary disease. MDI+VHC offers practical advantages over SVN, including the capacity for home use by the patient, portability, less setup time, and no need for daily disinfection. Pharmacists and respiratory therapists obtained approval through the pharmacy and therapeutics committee for respiratory therapists to convert orders for bronchodilators delivered by SVN to administration by MDI+VHC. The conversion policy allows physicians to override it, but none have exercised this option. On intensive care units (ICUs), the policy resulted in a 53% increase in the use of MDI+VHC during the six-month period after it went into effect. Respiratory therapists have been less thorough in implementing the policy for non-ICU patients. CONCLUSION: Delivery of bronchodilators by MDI+VHC is as effective as delivery by SVN but offers several advantages. A policy to switch patients from SVN to MDI+VHC for bronchodilator administration met with limited success.     

Inhaled corticosteroid delivery systems: clinical role of a breath-actuated device

Several devices have been developed to overcome the need to co-ordinate actuation with inhalation required during use of a pressurised metered dose inhaler (MDI) and to improve drug delivery to the lung. These include spacer attachments for MDIs, dry powder inhalers and breath-actuated MDIs. The breath-actuated Autohaler (3M Pharmaceuticals) is a compact, multidose inhaler device that, unlike dry powder inhalers, does not rely on the patient's inspiratory effort to aerosolise the dose of medication. Due to its simple operation, the Autohaler is suitable for patients unable to operate a conventional MDI efficiently, including the elderly, children, patients with arthritis and patients with low inspiratory flow rates. The mandatory replacement of chlorofluorocarbon propellants with non-ozone-depleting propellants has given the opportunity to improve drug delivery characteristics of MDIs. Recently, a formulation of beclomethasone dipropionate in hydrofluoroalkane-134a (HFA-BDP), has been developed in a conventional MDI that delivers most of the emitted dose to the lung. Drug deposition studies show that the HFA-BDP formulation in the Autohaler device has a similar lung deposition pattern to drug delivered from the MDI, when used correctly, and dose delivery is consistent across a wide range of inspiratory flow rates. Furthermore, HFA-BDP Autohaler has similar clinical benefits to CFC-BDP Autohaler but at less than half the dose. HFA-BDP Autohaler offers a useful CFC-free delivery option for patients challenged by the conventional MDI device.     

Particle size and charge distribution analysis of pharmaceutical aerosols generated by inhalers

Aerosol particles generated by inhalers for respiratory drug delivery acquire electrostatic charge during the dispersion process. The electrostatic charge distribution of the particles can affect the efficiency of drug delivery by influencing both the transport and deposition of inhaled particles in the human lung. To analyze the electrostatic charge acquired by the aerosol particles, two sets of metered-dose inhaler (MDI) and dry powder inhaler (DPI) devices were investigated. Both the particle size and charge distributions were measured simultaneously by using an electrical single-particle aerodynamic relaxation time (E-SPART) analyzer. The analyzer was calibrated with particles of known size, which were generated by a vibrating orifice aerosol generator (TSI Inc.) and charge using the Faraday cup method. The charge distributions of the pharmaceutical aerosols from both the DPI and MDI devices were bipolar in nature. Although the net charge-to-mass ratio was less than 0.2 microC/g, the individual particles were charged with a relatively high charge: -2 to + 2 microC/g. The count mean aerodynamic diameter of the aerosols generated from these devices was 3-5 microm.     

吸入装置辅导视频制作及效果评价

目的:评估用药辅导视频对提高离院患者吸入装置正确使用能力的效果。方法:制作空气压缩雾化机、压力定量气雾剂+储雾罐(面罩)和吸入粉雾剂(都保)的用药辅导视频,对用药辅导视频的使用效果进行问卷调查,每项调查选取100例患者,先让患者观看药品及空气压缩雾化机使用说明书,进行评分(评分1),后让患者观看视频后学习使用,进行评分(评分2)。应用SPSS 22.0统计学软件分析评分结果。结果:相较于单纯阅读说明书,辅导视频可以有效提高空气压缩雾化机(Z=-8.231,P<0.01)、压力定量气雾剂+储雾罐(面罩,Z=-8.518,P<0.01)和吸入粉雾剂(都保)的正确使用率(Z=-8.145,P<0.01)。结论:用药辅导视频可以有效提高患者正确使用空气压缩雾化机、压力定量气雾剂+储雾罐(面罩)和吸入粉雾剂(都保)的能力。     

Comparability of albuterol delivered by a piezoelectric device versus metered dose inhaler in patients with chronic obstructive airways disease.

In recent years, there has been increased interest in developing propellant-free inhalers for the treatment of patients with chronic obstructive airways disease. Various powder inhalators have been developed. A recent alternative to the dose-metered aerosols has been produced using the piezoelectric effect. This double-blind, double-dummy, randomized, dual-dose, four-period crossover study was designed to compare the effect of albuterol inhaled from the piezoelectric device (PED) and albuterol inhaled from the metered dose inhaler (MDI). The primary efficacy variables were forced expiratory volume in one second (FEV1) and area under the curve (AUC). Although we found a statistically significant device effect for the primary efficacy variables, the two treatments (PED [test] and MDI [reference]) are comparable. The only variable for which comparability was not found was time of onset. We found no dose differences. In conclusion, we found a similar effect of albuterol inhaled by a PED versus an MDI in patients with chronic obstructive airways disease.     

Effect of propellant on the pharmacokinetics and pharmacodynamics of inhaled albuterol in asthmatic subjects.

Hydrofluoroalkane (HFA) propellants have largely replaced chlorofluorocarbon (CFC) propellants in metered dose inhalers (MDI). It is important to document the pharmacokinetics (PK) and pharmacodynamics (PD) of medications delivered using HFA propellants compared to CFC propellants. Six adult asthmatics with mild to moderate asthma were selected for the study. Each subject inhaled 180 microg of albuterol from an MDI with holding chamber. Venous blood was collected for measuring albuterol levels at intervals over 12 h, and spirometric measurements of airflow were measured over the same time period. Plasma samples were analyzed using a GC/MS assay developed in our laboratory. PK and PD parameters were calculated by nonlinear regression using WinNonlin. There were no statistically significant differences between PD parameters for HFA versus CFC propellants. The area under the plasma albuterol concentration versus time curve (AUC) was 72% greater for the HFA formulation, indicating a greater lung bioavailability (p = 0.015). This difference in bioavailability did not result in a statistically significant difference in FEV(1) values between the two propellants.     

Investigating improving powder deagglomeration via dry powder inhalers at a low inspiratory flow rate by employing add-on spacers

The aim of this study was to investigate whether small add-on spacers alone or equipped with a passive deagglomerating component would improve aerosol performances of passive low airflow resistance dry powder inhalers (DPIs) at a low inhalation flow rate. Depositions of beclometasone dipropionate (BDP) and salbutamol sulphate (SS) via the Asmabec Clickhaler and Asmasal Clickhaler at 30 L/min airflow rate in an oropharyngeal model and attached filter were determined. Three add-on spacers, one with 5.0 cm length, and the other with the same features but incorporating a fine mesh, and the third one with the length of 8.5 cm (long add-on spacer) were used. Incorporating mesh did not improve the filter dose for SS, and significantly reduced this dose for BDP. The long add-on spacer was the most efficient spacer as it had minimal effects on the filter doses, also significantly reduced drug depositions in the model. In conclusion, an optimum length of an add-on spacer is required to minimise oropharyngeal drug deposition via a low airflow resistance DPI at a low inspiratory flow rate without considerable reduction of the respirable dose. Incorporating sieves within add-on spacers may diminish aerosol performances of the DPIs at low airflow rates.     

Large and small airway responses to procaterol hydrochloride administered through different extension devices in asthmatic patients.

The effects of spacer devices on the magnitude and velocity of large and small airway bronchodilator responses in asthmatic patients who can correctly operate a metered dose inhaler (MDI) remain unclear. According to a double-blinded, randomized, crossover protocol, 14 asthmatic patients were studied on seven separate occasions. On each occasion, patients inhaled doubling methacholine concentrations until forced expiratory volume in 1 second (FEV1) had fallen by 20% of baseline. Changes in forced expiratory flow between 25% and 75% of vital capacity (FEF25-75) were also evaluated. Subsequently, patients were administered 20 or 50 micrograms of procaterol from an MDI either alone or in conjunction with a small- or large-volume spacer device. Changes in FEV1 and FEF25-75 corrected for baseline forced vital capacity (isoFEF25-75) were assessed at 3-minute intervals for 15 minutes and at 30 minutes. Spontaneous recovery was similarly evaluated. The time required to attain significant increases in both FEV1 and isoFEF25-75 was calculated in bronchodilator trials. With 20 micrograms of procaterol, both spacers allowed larger and faster FEV1 increases than the MDI alone (P < 0.01); with 50 micrograms, the velocity and magnitude of FEV1 increases were further enhanced in trials with the MDI alone. The lower procaterol dose via the large-volume spacer determined larger and faster isoFEF25-75 increases than the higher dose via both the small-volume spacer and the MDI alone (P < 0.01). Spacers enhance bronchodilation even in patients using MDIs optimally. Compared with both the small-volume device and the MDI alone, the large-volume spacer allows faster and larger small airway dilation with less than half of the procaterol dose.     

Evaluation of levalbuterol metered dose inhaler in pediatric patients with asthma: a double-blind, randomized, placebo- and active-controlled trial

OBJECTIVE: To evaluate the efficacy and safety of levalbuterol metered dose inhaler (MDI) in children aged 4-11 years (n = 173). RESEARCH DESIGN AND METHODS: Multicenter, randomized, double-blind 28-day study of QID levalbuterol 90 microg, racemic albuterol 180 mug, and placebo (2:1:1 ratio). Serial spirometry was performed on Days 0, 14, and 28. The primary endpoint was the double-blind average peak percent (%) change in FEV(1) from visit pre-dose; the primary comparison was with placebo. Secondary endpoints included the area under the FEV(1) percent change from pre-dose curve and peak % predicted FEV(1). Safety endpoints included adverse events, laboratory tests, rescue medication use, and electrocardiograms. RESULTS: Levalbuterol significantly improved the least square mean peak percent change in FEV(1) compared with placebo (levalbuterol 25.6% +/- 1.3% [p < 0.001]; racemic albuterol 21.8% +/- 1.8% [p = ns]; placebo 16.8% +/- 1.9%). Results for levalbuterol were similar for the other spirometry endpoints (p < 0.05 vs. placebo). No levalbuterol-treated patients had a peak percent change in FEV(1) < 10% (compared with 15.8% of racemic albuterol-treated patients and 30.3% of placebo-treated patients). The incidence of adverse events was 43.4% for levalbuterol, 56.4% for racemic albuterol, and 51.4% for placebo. The rate of discontinuation was 1.3% for levalbuterol, 2.6% for racemic albuterol, and 8.6% for placebo. The rate of asthma attacks (10.5%, 12.8%, 14.3%, respectively) was similar among treatments. Levalbuterol and racemic albuterol both reduced rescue medication use (p < 0.01 vs. placebo) and produced changes in ventricular heart rate and QT(c-F) that were similar to placebo. CONCLUSIONS: In this study, levalbuterol administered via MDI significantly improved airway function in comparison with placebo in asthmatic children aged 4-11 years with a safety profile that was similar to placebo.     

Metering performance of several metered-dose inhalers with different spacers/holding chambers.

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.     

Evaluation of SCF-engineered particle-based lactose blends in passive dry powder inhalers

The objective of this study was to assess the performance of SCF-engineered budesonide and albuterol sulfate powder blends in passive dry powder inhalers (DPI) relative to micronized drug blends. A number of lactose grades for inhalation were screened and the appropriate carrier and drug-to-lactose blending ratio were selected based on drug content and emitted dose uniformity. Aerosol performance was characterized by Andersen cascade impaction. Blend formulations of SEDS (solution enhanced dispersion by supercritical fluids) budesonide and albuterol exhibited a significant drug content uniformity (7-9% RSD) improvement over micronized drug blends (16-20% RSD). Further, the SEDS formulations demonstrated higher emitted dose and reduced emitted dose variability (10-12% RSD) compared to micronized powders (21-25% RSD) in the Turbospin, albeit without significant enhancement of the fine particle fraction. In contrast, SEDS powders exhibited increased fine particle fractions over micronized blends in the Clickhaler; improvements were more pronounced with albuterol sulfate. The performance enhancements observed with the SEDS powders are attributed to their increased surface smoothness and reduced surface energy that are presumed to minimize irreversible drug-carrier particle interactions, thus resulting in more efficient drug detachment from the carrier particle surface during aerosolization. As demonstrated for budesonide and albuterol, SEDS may enhance performance of lactose blends and thus provide an attractive particle engineering option for the development of blend formulations for inhalation delivery.     

Chromosome aberrations induced by benzo(a)pyrene in a feeder cell-mediated assay

Studies were made on chromosome aberrations induced by benzo(a)pyrene (Bp) in V79 cells in the presence or absence of feeder cells. In the presence of feeder cells, chromosome aberrations at Bp concentrations of 1.0–20.0 μg/ml depended on feeder cell density. The highest incidences of chromosome aberrations (aberrant cells) and of aberrant chromosomes per 100 metaphase cells were 24.0% and 38.0%, respectively, and were obtained at 20.0 μg/ml Bp in the presence of 2.0 · 10⁶ feeder cells/60-mm plastic dish. In the absence of feeder cells, chromosome aberrations were not induced; the incidences of aberrant cells and chromosomes on treatment with Bp in the absence of a feeder layer were 3.0–5.0 and 3.0–6.0%, respectively, while the spontaneous rates (of both) were 5.0%.     

A Novel Method to Aerosolize Powder for Short Inhalation Exposures at High Concentrations: Isolated Rat Lungs Exposed to Respirable Diesel Soot

More efficient methods are needed to aerosolize dry powders for short-duration inhalation exposures at high concentrations. There is an increasing need to reach the peripheral lung with dry powder medications as well as with collected ambient aerosol particulates in environmental research projects. In a novel aerosol generator, a fixed volume of compressed air was used to create a short burst of a highly concentrated aerosol in a 300-ml holding chamber. Collected diesel soot was deagglomerated to a fine aerosol with a mass median aerodynamic diameter (MMAD) of 0.55 μm, not much larger than the 0.25 μm MMAD of diesel exhaust particles measured in air. A fine powder such as 3-μm silica particles was completely deagglomerated to an aerosol with a MMAD of 3.5 μm. Immediately after generation, the aerosol was available for exposure at a chosen flow rate by the use of an automated valve system. Tritium-labeled diesel soot was thus used to expose the isolated perfused rat lung at an air concentration of ～3 mg/L and a flow rate of 370 ml/min in a 1-min-long exposure. The lungs were ventilated at 75 breaths/min and a tidal volume of 1.13 ± 0.11 ml (SD, n = 3). Results showed that 19.8 ± 1.1 μg (SD, n = 3) soot was deposited in the lungs. This amount constitutes 9.5% of the amount inhaled and is close to literature data on deposition of similar sized particles in the rat lung. More than 97% of the deposited soot was located distal to the extrapulmonary bronchi, indicating that the system delivers a highly respirable aerosol. The aerosol system is particularly useful for peripheral lung delivery of collected ambient aerosols or dry powder pharmaceuticals following a minimal effort in formulation of the powder.     

Relative bioavailability of a controlled-release albuterol formulation for twice-daily use

A two-way-crossover bioavailability study was completed with 15 healthy male volunteers to evaluate the relative bioavailability of an orally administered controlled-release (CR) formulation of albuterol as compared to the immediate-release (IR) formulation of albuterol. The CR formulation of albuterol used in this study was based mechanistically on the elementary osmotic pump. Each subject received one 8 mg CR tablet every 12 h for 8 consecutive days and one 4 mg IR tablet every 6 h for 8 consecutive days, with 7 days separating each phase. During day 8 of dosing, hourly blood samples (0-12 h) were collected after the morning dose and three additional samples were obtained 16, 20 and 24 h following this dose. Plasma concentrations were measured using a gas chromatography-mass spectrometry procedure. No statistically significant differences were observed in mean steady-state values for Cmax, Cmin, AUC(0-12 h) and peak-to-trough fluctuations (PTF) in comparing the two dosage formulations. Mean steady state Tmax values were 2.6 and 6.0 h for the TR and CR formulations, respectively. It was concluded that twice daily administration of the controlled-release formulation of albuterol provides an alternative to four times daily administration of conventional (immediate-release) albuterol tablets.