Lars Borgström

Lung deposition of budesonide inhaled via Turbuhaler: a comparison with terbutaline sulphate in normal subjects

We wanted to evaluate whether lung deposition of budesonide and terbutaline sulphate differs, and to determine lung deposition of budesonide inhaled at different peak inspiratory flows, through Turbuhaler. Lung deposition of budesonide, a lipophilic substance, and of terbutaline sulphate, a hydrophilic substance, was therefore compared, after administration via an inspiratory flow-driven, multi-dose, powder inhaler (Turbuhaler, Astra Draco AB) to 10 healthy volunteers. The radionuclide 99mTc was used to label drug particles, and radioactivity, indicating drug deposition, was measured using a gamma camera. Budesonide was inhaled at a normal flow of 58 l.min-1 and at a slow flow of 36 l-min-1. At the faster flow, a mean +/- SD 27.7 +/- 9.5% of the metered dose was deposited in the lung and at the slower flow 14.8 +/- 3.3% was deposited (p < 0.001). Mean lung deposition of terbutaline sulphate inhaled at 57 l.min-1 was 27.0 +/- 7.7%. We conclude that inspiratory flow has an important effect on lung deposition, but water solubility appears to have no effect.

Airway deposition and airway effects of antiasthma drugs delivered from metered-dose inhalers

Many different metered-dose inhalation devices are becoming available for the treatment of airway diseases. Each of these inhalers differs in its delivery characteristics. An assessment of the efficacy of drug delivery by these inhalers is essential, in view of their therapeutic use. A review of the literature on the relationship between airway deposition and airway effects of drugs delivered from metered-dose inhalers is presented. Nebulizers or spacers are not discussed. The effect of an inhaler depends on the characteristics of the inhaler and the inhalation manoeuvre performed by the patient. This review focuses on the influence of inhaler characteristics on the airway deposition and airway effects. Data from several studies show that there is a significant relationship between the amount of drug deposited in the airways and the airway effects of the drug. Studies on the relationship between airway deposition and airway effect have been troubled by methodological problems, such as the absence of multiple dose comparisons and the difficulty in obtaining steep dose-response curves. The techniques for measuring airway deposition of inhaled drugs, namely the scintigraphic and the pharmacokinetic method, are discussed and compared. The appropriate use of these techniques can help to define and compare the drug delivery characteristics of different devices, thus enabling inhaled therapy to be optimized.

Variability in lung deposition of inhaled drug, within and between asthmatic patients, with a pMDI and a dry powder inhaler, Turbuhaler ®

In vitro analysis of inhaled formulations measures, among other parameters, the variability in delivered dose, while a corresponding in vivo analysis also includes the variability caused by patient performance and distribution of drug between the oropharynx and the lungs. In vitro, the dose variability is higher for Turbuhaler(R) than for the corresponding pMDI, whereas in vivo, the converse is true: the variability in lung deposition is significantly higher, both between and within subjects, for pMDI than for Turbuhaler. The observation can be due to several factors such as the non-continuous working principle of inhalation via pMDI as opposed to the continuous working principle of inhalation via Turbuhaler.

Validation of a General In Vitro Approach for Prediction of Total Lung Deposition in Healthy Adults for Pharmaceutical Inhalation Products

BACKGROUND A validated method to predict lung deposition for inhaled medication from in vitro data is lacking in spite of many attempts to correlate in vitro and in vivo outcomes. By using an in vivo-like in vitro setup and analyzing inhalers from the same batches, both in vitro and in vivo, we wanted to create a situation where information from the in vitro and in vivo outcomes could be analyzed at the same time. METHOD Nine inhalation products containing either budesonide or AZD4818 were evaluated. These comprised two pressurized metered dose inhalers (pMDIs), a pMDI plus a spacer, four dry powder inhalers, and two dosimetric nebulizers. In vitro, an in vivo-like setup consisting of anatomically correct inlet throats were linked to a flow system that could replay actual inhalation flow profiles through the throat to a filter or to an impactor. In vivo, total lung deposition was measured in healthy adults by pharmacokinetic methods. RESULTS AND CONCLUSION We could show that the amount of drug escaping filtration in a realistic throat model under realistic delivery conditions predicts the typical total lung deposition in trained healthy adult subjects in the absence of significant exhaled mass. We could further show that by using combinations of throat models and flow profiles that represent realistic deviations from the typical case, variations in ex-cast deposition reflect between-subject variation in lung deposition. Further, we have demonstrated that ex-cast deposition collected either by a simple filter or by a cascade impactor operated at a fixed flow rate using a mixing inlet, to accommodate a variable flow profile through the inhaler, predicts equally well the lung deposited dose. Additionally, the ex-cast particle size distribution measured by this method may be relevant for predicting exhaled fraction and regional lung deposition by computational models.

On the Use of Dry Powder Inhalers in Situations Perceived as Constrained

Dose delivery from dry powder inhalers (DPIs) are dependent on the inhalation effort of the patient. Some patient groups, including asthmatic children, patients with acute asthma, and patients with advanced chronic obstructive pulmonary disease (COPD) are perceived as having problems in readily inhaling from a DPI in an efficient way; this opinion is based on alleged low inhalation flows. A review of the literature however shows that these groups can use a DPI in an efficient way and gain good clinical effect from its use. Particularly, it has been shown that children can generate a good peak inhalation flow through a DPI, albeit a lower inhaled volume. Similarly, patients with acute asthma can use a DPI in an efficient way, even reaching a better clinical effect with the DPI than with a pressurized metered dose inhaler with a spacer. Finally, it was shown that patients with severe COPD can generate the inhalation flows needed to generate an efficient drug aerosol from a DPI. Collectively, the discussed patient groups seem to perform as well as other subjects when it comes to their ability to generate an adequate inhalation flow through a DPI.

The bioavailability and airway clearance of the steroid component of budesonide/formoterol and salmeterol/fluticasone after inhaled administration in patients with COPD and healthy subjects: a randomized controlled trial

BackgroundAirway absorption and bioavailability of inhaled corticosteroids (ICSs) may0020be influenced by differences in pharmacokinetic properties such as lipophilicity and patient characteristics such as lung function. This study aimed to further investigate and clarify the distribution of budesonide and fluticasone in patients with severe chronic obstructive pulmonary disease (COPD) by measuring the systemic availability and sputum concentration of budesonide and fluticasone, administered via combination inhalers with the respective long-acting β2-agonists, formoterol and salmeterol.MethodsThis was a randomized, double-blind, double-dummy, two-way crossover, multicenter study. Following a run-in period, 28 patients with severe COPD (mean age 65 years, mean forced expiratory volume in 1 second [FEV1] 37.5% predicted normal) and 27 healthy subjects (mean age 31 years, FEV1 103.3% predicted normal) received two single-dose treatments of budesonide/formoterol (400/12 μg) and salmeterol/fluticasone (50/500 μg), separated by a 4–14-day washout period. ICS concentrations were measured over 10 hours post-inhalation in plasma in all subjects, and over 6 hours in spontaneously expectorated sputum in COPD patients. The primary end point was the area under the curve (AUC) of budesonide and fluticasone plasma concentrations in COPD patients relative to healthy subjects.ResultsMean plasma AUC values were lower in COPD patients versus healthy subjects for budesonide (3.07 μM·hr versus 6.21 μM·hr) and fluticasone (0.84 μM·hr versus 1.50 μM·hr), and the dose-adjusted AUC (geometric mean) ratios in healthy subjects and patients with severe COPD for plasma budesonide and fluticasone were similar (2.02 versus 1.80; primary end point). In COPD patients, the Tmax and the mean residence time in the systemic circulation were shorter for budesonide versus fluticasone (15.5 min versus 50.8 min and 4.41 hrs versus 12.78 hrs, respectively) and Cmax was higher (1.08 μM versus 0.09 μM). The amount of expectorated fluticasone (percentage of estimated lung-deposited dose) in sputum over 6 hours was significantly higher versus budesonide (ratio 5.21; p = 0.006). Both treatments were well tolerated.ConclusionThe relative systemic availabilities of budesonide and fluticasone between patients with severe COPD and healthy subjects were similar. In patients with COPD, a larger fraction of fluticasone was expectorated in the sputum as compared with budesonide.Trial registrationTrial registration number NCT00379028

Idealhalers or realhalers? A comparison of Diskus and Turbuhaler

Medication for the treatment of asthma and chronic obstructive pulmonary disease should be given locally by inhalation. There is, however, no such thing as an ideal inhaler, or ‘Idealhaler’, which has all desired properties with no drawbacks. In this short review, we have compared the relative merits of the two most commonly used dry powder inhalers – Turbuhaler® and Diskus™. Clinical effect is related to the amount of inhaled drug that reaches the lungs, and this in turn depends on the amount of fine particles generated at inhalation. Turbuhaler® is more than twice as effective as Diskus™ at generating fine particles, and the higher lung deposition with Turbuhaler® is accompanied by a lower variability in lung deposition. Compared with Diskus™, the lung deposition with Turbuhaler® is affected less by factors such as humidity.

Pharmacokinetics of Budesonide and Formoterol Administered Via 1 Pressurized Metered-Dose Inhaler in Patients With Asthma and COPD

In 3 open‐label studies, the systemic bioavailability of budesonide and formoterol administered via pressurized metered‐dose inhaler (pMDI) or dry powder inhaler (DPI) formulations was evaluated in asthma (24 children, 55 adults) or chronic obstructive pulmonary disease (COPD; n =26) patients. Treatments were administered at doses high enough to estimate pharmacokinetic parameters reliably. Two of the studies included an experimental budesonide pMDI formulation. In study 1 (asthma, adults), budesonide area under the curve (AUC) was 32% and 31% lower and maximal budesonide concentration (Cmax) 45% and 56% lower after budesonide/formoterol pMDI and budesonide pMDI versus budesonide DPI. Formoterol AUC and Cmax were 13% and 39% lower after budesonide/formoterol pMDI versus formoterol DPI. In study 2 (asthma, children), budesonide AUC and Cmax were 27% and 41% lower after budesonide/formoterol pMDI versus budesonide DPI + formoterol DPI. In study 3 (COPD/asthma, adults), budesonide AUC and Cmax were similar and formoterol AUC and Cmax 18% and 22% greater after budesonide/formoterol pMDI versus budesonide pMDI + formoterol DPI (COPD). Budesonide and formoterol AUC were 12% and 15% higher in COPD versus asthma patients. In conclusion, systemic exposure generally is similar or lower with budesonide/formoterol pMDI versus combination therapy via separate DPIs or monotherapy and comparable between asthma and COPD patients.

Planar gamma scintigraphy—points to consider when quantifying pulmonary dry powder aerosol deposition

Methodological aspects of planar gamma scintigraphy used to quantify pulmonary aerosol deposition were investigated using an experimental dry powder formulation. Particles of micronized salbutamol sulphate were labelled with technetium-99m and admixed to an ordered mixture of unlabelled micronized salbutamol sulphate and larger carrier particles of lactose. The radioaerosol was administered to 24 healthy subjects, 12 in each of two consecutive, similarly designed studies. Pulmonary deposition was determined using two methods: repeated planar imaging, and pharmacokinetic assessments following charcoal co-administration to prevent gastrointestinal salbutamol absorption. After due consideration had been taken to ensure appropriate radiolabelling, image acquisition and processing procedures, a scintigraphic estimate of 26.2% (with 95% confidence interval of 24.2-28.4%) was obtained, which did not significantly differ from the pharmacokinetic estimate of 26.4% (24.4-28.7%). In summary, pre-study validation of the radiolabelling technique, quality control of radioaerosols produced during the study, correction for re-distribution of radiolabel from the lungs, selection of regions of interest, assessment of lung contours, correction for tissue attenuation of gamma rays and establishment of the actual recovery of radioactivity in the scintigraphic measurements could potentially affect the accuracy of the scintigraphic estimate of pulmonary deposition and, thus, should be carefully considered in the design or evaluation of any such study.

Use of dry powder inhalers in acute exacerbations of asthma and COPD

To investigate whether dry powder inhalers (DPIs) function in a constrained situation, a literature analysis was performed to evaluate the use of DPIs compared with established therapies in the treatment of acute asthma and COPD, irrespective of rapid-acting β2-agonist used. The external databases Medline, Embase, Biosis and Current Contents and AstraZenecas internal literature database Planet were searched up to April 2008. Only publications or congress abstracts describing clinical trials in patients treated at EDs or hospitals were considered, and then only those in which exacerbation severity (measured as FEV1) were included. Fifteen clinical studies met these criteria; twelve in acute asthma and three in acute COPD. For acute asthma, eight studies were double-blind, randomised studies (six in adults and two in children), two were open-label studies (one in adults and one in children), and two were investigational (methacholine challenge) studies. For the acute COPD studies, one was double-blind and randomised, one was single-blind and randomised, and one was open-label. This review found that administration of fast-acting bronchodilators via DPIs, the majority of which were Turbuhaler, is effective during an asthma or COPD worsening. Our literature review finds that DPIs function in patients with acute asthma or COPD equally well as established therapies with other inhaler devices. Patients can therefore rely upon DPIs in the same way that they rely upon other inhaler devices.