Developing and advancing dry powder inhalation towards enhanced therapeutics.

Enhanced therapeutics are drug products derived from existing generic drugs that provide additional benefits to the patients and the healthcare system. Enhanced therapeutics are considered to be an important and relatively low risk source of innovation. Pulmonary drug delivery is the major delivery route to treat chronic respiratory diseases and has been proven as a potential delivery route for complex drugs that cannot be delivered orally. Development of dry powder inhalation systems targets the delivery of fine drug particles to the deep lung surface by a combination of drug formulation, primary packaging and a device, whereby each contributes to the overall performance. Various methodologies for the non-clinical and clinical performance testing of orally inhaled products have been proposed and applied with variable success. Regulatory pathways have been developed and applied since. Considerable efforts have been made during the past decade to understand and optimize pulmonary drug delivery including their efficient commercial manufacturing. Pulmonary drug delivery remains an area of future innovation in the effective treatment of pulmonary diseases as well as the systemic delivery of systemically active complex drugs.

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.

Lung deposition and protective effect of terbutaline delivered from pressurized metered-dose inhalers and the Turbuhaler in asthmatic individuals.

We investigated the relationship between pulmonary deposition of terbutaline and bronchoprotection against methacholine and histamine with the Turbuhaler (AstraZeneca, Lund, Sweden) and a pressurized metered dose inhaler (pMDI) in 13 asthmatic patients. The study was done with a randomized, double blind, double dummy, and crossover design. On different days, the provocative concentration of histamine causing a 20% decrease in FEV(1) (PC(20) histamine) and PC(20) methacholine were determined before and at 1.5, 3, and 6 h after inhalation of 0.25 or 0.5 mg of terbutaline sulfate. The Turbuhaler delivered significantly more drug than did the pMDI (% of the nominal metered dose and 95% confidence interval): 20.8% (16.4 to 26.6%) and 16.9% (13.2 to 21.7%) versus 4.8% (3.8 to 6.1%) and 7.4% (5.8 to 9.5%), respectively. Average protection against histamine over 6 h was 0.66 (95% CI: 0.45 to 0.87) doubling concentrations (DC) after inhalation of 0.25 mg and 1.08 (95% CI: 0.87 to 1.29) DC after 0.5 mg terbutaline via pMDI, and 1.07 (95% CI: 0.87 to 1.29) DC after 0.25 mg and 1.24 (95% CI: 1.03 to 1.45) DC after 0.50 mg via Turbuhaler. Protection against methacholine was also dose- and device-dependent. The dose needed to obtain the same pulmonary deposition with the pMDI was 3.14 times greater than with the Turbuhaler, and that needed for the same protective effect was 2.1 and 3.2 times greater for histamine and methacholine, respectively. We conclude that pulmonary deposition of terbutaline was predictive of the clinical response.

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.

Pulmonary clearance rate of two chemically different forms of inhaled pertechnetate.

Attempts to image the pulmonary deposition site of radiolabeled aerosols delivered by dry powder inhalers (DPIs) and pressurized metered-dose inhalers (pMDIs) using single photon emission computed tomography (SPECT) have been limited by the rapid pulmonary clearance of radiolabel. To determine whether aqueous solubility of the radiolabel is a significant factor, the pulmonary clearance rates of two chemically different forms of 99mTc were calculated. A dry powder formulation of terbutaline sulphate was radiolabeled for inhalation by Turbuhaler (AstraZeneca) using the water-soluble salt sodium pertechnetate and the water-insoluble salt tetraphenylarsonium pertechnetate. A pilot study was conducted during which two control subjects each inhaled the two radiolabeled aerosols on separate days. Intrasubject clearance rates for the two species were very similar. It was therefore concluded that water insolubility of the pertechnetate salt alone was not enough to extend the lung residency time of the radiolabel.

The importance of the device in asthma therapy.

Inhalation is the preferred route for drug delivery in asthma treatment. Successful management of asthma depends on achieving adequate delivery of inhaled drug to the lungs, and to this end the role of the device used for delivery is very important. Aerosolized anti-asthma medications have been available for more than 40 years as pressurized metered dose inhalers (pMDIs), but more recently dry powder inhalers (DPIs) have been developed as an alternative. Laboratory assessment of fine particle dose has been shown to correlate to pulmonary deposition if the assessments are performed with an in vivo-like set up. The DPI Turbuhaler delivers a high proportion of the dose as fine particles suggesting high pulmonary deposition. This finding has been confirmed by lung deposition studies, which indicate superior pulmonary deposition from Turbuhaler compared with a pMDI. This superior delivery to the lungs with Turbuhaler is reflected in a better clinical effect, as measured by greater improvements in lung function. The DPIs such as Turbuhaler are easy to use, and Turbuhaler has been shown to function well in a constrained situation such as an acute asthmatic exacerbation. Furthermore, the use of Turbuhaler in acute asthma will provide rapid clinical improvement. The in vivo variability in lung deposition obtained with Turbuhaler is lower than with pMDI, indicating that the performance of Turbuhaler is less dependent on patient competence. Thus, the development of Turbuhaler represents an important step forward in the effective management of asthma.

Cumulative and single-dose design to assess the bronchodilator effects of beta2-agonists in individuals with asthma.

With the development of different chlorofluorocarbon (CFC)-free metered dose aerosol and dry powder devices, it is necessary to study and validate the methods used for assessing and comparing their efficacy. This study evaluated the cumulative dose design by determining the bronchodilator response to salbutamol given according to either a high or a low cumulative dose regimen. Adults with asthma (n = 24) were studied in a placebo-controlled, randomized, double-blind, cross-over design. On separate days, cumulative doses of salbutamol (50+50+100+200 or 100+100+ 200+400 or 400+0+0+0 or 0+0+0+0 microg) were given via Turbuhaler with 30 min between doses. The two cumulative dose regimens produced almost identical bronchodilator responses at each time point. The relative dose-potency between the 800- and 400- microg cumulative dose regimens was 0.7 with a 95% confidence interval of 0.5-1.0, excluding the true value of 2. The 400-microg cumulative dose regimen resulted in a higher FEV1 at 115 min than the 400-microg single-dose regimen. There was no difference in the bronchodilator response to the single dose of 50, 100, or 400 microg of salbutamol after either 5 or 25 min. Thus, care should be exercised when using either a cumulative or single-dose design for comparing different beta2-agonists, or different inhalation devices, with respect to their relative dose-potency. In addition, this study provides further evidence that for short-acting beta2-agonists such as salbutamol, lower doses than those normally recommended may be used, and that repeated self-administration of low doses over a period of 60 min may give a better bronchodilator response than a single administration of a high dose.

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.

The pharmacokinetics of inhaled hydrofluoroalkane formulations.

To obtain the full picture of a formulation, the in vitro and the in vivo information can be looked upon as components of a "prediction bridge" where the in vitro information can be used to predict lung deposition, which in turn can be used to predict clinical outcome. This bridging concept can be used as a template to evaluate new information on emerging inhaled formulations. The concept was used to evaluate literature data on new hydroflouroalkane formulations of salbutamol and beclomethasone dipropionate (BDP). The new salbutamol hydroflouroalkane formulations seem to have properties similar to those of the old chlorofluorocarbon formulations even if the presented information on effect comparisons is limited. The first BDP hydroflouroalkane formulation is a solution formulation with in vitro properties that are quite different from those of the old chlorofluorocarbon suspension formulation. The BDP hydroflouroalkane formulation has a much greater fine particle mass, which eventually results in greater lung deposition and better clinical effect.

In vitro, ex vivo, in vivo veritas.

In vitro assessments of inhaler performance are important in product development and quality control, but are not, as such, good predictors of performance in vivo. It is, however, possible to modify in vitro techniques so that they more closely resemble the in vivo situation. Measurements of fine-particle dose (defined as the amount of drug with an aerodynamic diameter less than 5 microm) by cascade impactor have shown that the measured fine-particle dose in vitro is highly dependent on the geometry of the inlet to the impactor, the fine-particle dose being considerably lower when the cast of a human throat (an "anatomical throat") is used than when a standard glass inlet is used. This difference is, however, less with a dry-powder inhaler such as Turbuhaler than with a pressurized metered-dose inhaler (pMDI). Furthermore, there is a good correlation between fine-particle dose measured in vitro and in vivo lung deposition, provided that an anatomically correct inlet is used for the in vitro determination. Studies in children have shown that the degree of lung deposition of budesonide, delivered via Turbuhaler, is of the same order of size as the in vitro fine-particle dose. No comparable data are available for pMDIs; however, since children are smaller than adults, it is likely that differences in lung deposition between Turbuhaler and pMDIs are probably greater in children than in adults.

The effects of static charge in spacer devices on glucocorticosteroid aerosol deposition in asthmatic patients.

Electrostatic charge in plastic spacer devices has been shown in vitro to reduce delivery of asthma medications intended for inhalation, but the effect of static charge on in vivo drug deposition is unknown. A six-way randomized crossover study was conducted in 10 mild asthmatic patients. Two plastic spacers (Nebuhaler and Volumatic) and one metal spacer (Nebuchamber) were tested. The spacers were used either "primed" or "unprimed". Priming was performed by firing 20 doses of placebo aerosol into a new spacer, hence coating the inner surface with surfactant and minimizing static charge. Unprimed spacers were new and were not treated. Pressurized aerosol canisters delivering budesonide (200 microg Pulmicort) were radiolabelled with the radionuclide 99mTc and lung deposition was measured by gamma scintigraphy. The radiolabel was shown to be a valid marker for the drug substance prior to the clinical phase of the study. Priming significantly increased mean whole lung deposition following inhalation from plastic spacers (Nebuhaler primed 37.7% and unprimed 26.7%, p=0.01; Volumatic primed 32.0% and unprimed 22.1%, p=0.02). Priming had no effect on the mean whole lung deposition following inhalation from the Nebuchamber (primed 33.5% and unprimed 32.9%). Lung deposition in vivo from plastic spacer devices will vary according to the electrostatic charge on the spacer walls. Priming reduces retention of drug on plastic spacer devices and increases lung deposition. Metal spacers are not susceptible to static charge, which should result in more predictable lung deposition.

Lung deposition of budesonide from turbuhaler in asthmatic children.

UNLABELLED: The aim of our study was to evaluate the effect of age on lung deposition of radiolabelled budesonide, delivered as a dry powder via Turbuhaler to asthmatic children. A group of 23 asthmatic children, aged 6 to 16 years, with relatively stable asthma inhaled 99mTc-labelled budesonide from a dry powder inhaler (Turbuhaler). Body and lung deposition was assessed using a gamma camera. The mean (range) median peak inspiratory flow during inhalation was 65 1 x min(-1) (45 to 76 1 x min(-1)). Mean (range) total lung deposition of 99mTc-labelled budesonide, expressed as a percentage of the metered dose, was 29.1% (15.6-47.2%) and was positively and significantly correlated with age, height and peak inspiratory flow. CONCLUSION: Total lung deposition of radiolabelled budesonide from a dry powder inhaler (Turbuhaler), is age dependent in children with moderate asthma. However, lung deposition is still satisfactory, even in younger children with lower peak inspiratory flows.

Local versus total systemic bioavailability as a means to compare different inhaled formulations of the same substance.

For inhaled formulations of a drug substance, the balance between desired local activity and undesired systemic activity can be expressed with an L:T ratio, where L stands for the local bioavailability and T stands for the total systemic bioavailability. The L:T ratio depends not only on the ability of the different devices to divide the delivered dose between the lungs and the oropharynx but also on the inherent difference in gastrointestinal (GI) first-pass metabolism between different substances. The L:T ratio should therefore not be used to make comparisons across different drug substances but only to compare the same drug formulated in different inhalation systems. A high L:T ratio expresses a good targeting ability of the combination of substance and device or a low contribution from the GI tract. A high L:T ratio also reflects a more beneficial balance between wanted and unwanted effects. The L:T ratio was calculated from literature data for a number of salbutamol (albuterol) formulations and for two budesonide and two terbutaline formulations. For salbutamol, values ranged from 0.15 to 0.55 with different devices. For budesonide, the values ranged from 0.66 to 0.85, and for terbutaline, the values ranged from 0.59 to 0.79. The L:T ratio can thus be used to aid in the choice of inhaler.

Lung deposition from the Turbuhaler in children with cystic fibrosis.

Drug delivery to patients using dry powder inhalers, such as the Turbuhaler, is believed to be influenced by the inspiratory flow used. Clinical studies have indicated that this delivery system can be used effectively by children. However, it is not known how the total and weight-corrected dose delivered to the airways varies with age. A deposition study using technetium-99m (99mTc)-labelled budesonide was performed in order to determine the effect of age on delivery. Twenty one children with cystic fibrosis, aged 4-16 yrs, were recruited. They were clinically stable with normal lung function. Initially, a gamma camera scan was taken in front of a flood source containing 37 MBq of 99mTc. Subsequently, subjects inhaled through a low resistance inspiratory filter connected to a commercially available Turbuhaler. Immediately afterwards they inhaled from a noncommercial Turbuhaler containing budesonide labelled with 99mTc, and then underwent anterior and posterior gamma camera scans. Both Turbuhaler inhalers were attached to a portable spirometer and the peak inspiratory flow through the Turbuhaler was recorded for each inhalation. The total body dose was calculated from the dose deposited on the inspiratory filter connected to the commercial Turbuhaler. Analysis of the gamma camera images provided information on the proportion of the radiolabel delivered to the lungs compared to that deposited in the upper airway and stomach. As expected, a highly significant positive correlation was noted between the peak inspiratory flow generated by the patient through the Turbuhaler and the dose delivered to the lung. Similarly, there was a highly significant positive correlation between age and "total lung dose". However, when total lung dose was corrected for body weight, there was a nonsignificant negative correlation with age. This study suggests that the "weight-corrected lung dose" achieved when children aged > 6 yrs use the Turbuhaler, is largely independent of age. It would appear that the flow-dependent properties of this device are such that the reduced peak inspiratory flow generated by younger children results in a lower dose to the lungs, but that this is off-set by their lower body weight. This is unlikely to be a property of other devices with different flow/drug delivery characteristics.

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.

The inhalation device influences lung deposition and bronchodilating effect of terbutaline.

The development of new inhalation devices for asthma drugs raises the issue of the relationship between pulmonary deposition and therapeutic effect of inhaled drugs in patients with obstructive lung diseases. We thus conducted a randomized, double-blind and double-dummy, four-period crossover study in 13 patients with moderate asthma (mean age 36 yr; FEV1 59% of predicted), who inhaled 0.25 and 0.5 mg terbutaline sulphate on separate occasions either via a pressurized metered dose inhaler (pMDI) or Turbuhaler (TBH). Pulmonary deposition was 8.1 +/- 2.7% and 8.3 +/- 2.3%, respectively, of the nominal dose for pMDI and 19.0 +/- 7.3%, and 22.0 +/- 8.1% for TBH. The FEV1 increase after 0.25 mg terbutaline sulphate via TBH was significantly greater than after 0.25 mg via pMDI. No significant differences in FEV1 increase were observed between 0.25 mg via TBH, 0.5 mg via pMDI, or 0.5 mg via TBH. Other lung function variables showed similar dose- and device-related changes. We concluded that: (1) the dose of terbutaline sulphate deposited in the lungs is dependent on which inhalation system is used; (2) TBH delivers about twice the amount of drug to the lungs as the pMDI; and (3) the observed difference in deposition is reflected in the bronchodilating effect.

Comparison of gamma scintigraphy and a pharmacokinetic technique for assessing pulmonary deposition of terbutaline sulphate delivered by pressurized metered dose inhaler.

A comparison has been made of pulmonary deposition of terbutaline sulphate from a pressurized metered dose inhaler (pMDI), measured in 8 healthy male subjects by gamma scintigraphy and by a pharmacokinetic (charcoal-block) method, involving drug recovery in urine. Measurements were carried out with a pMDI at slow (27 l/min) and fast (151 l/min) inhaled flows and with Nebuhaler large volume spacer device (average inhaled flow 17 l/min). Overall, the two methods did not differ significantly in their estimates of whole lung deposition, although values obtained by gamma scintigraphy exceeded those from the charcoal-block method for the pMDI with fast inhalation. The regional distribution of drug within the lungs and deposition in the oropharynx could be assessed by gamma scintigraphy, but not by the charcoal-block method. It is concluded that either method may be used to assess whole lung deposition of terbutaline sulphate from pMDIs, both with and without a spacer, although each method has its own inherent advantages and disadvantages.

The lack of effect of induced net fluid absorption on the in vivo permeability of terbutaline in the human jejunum.

The absorption mechanism(s) of terbutaline in the human jejunum was studied by using the intestinal perfusion instrument, Loc-I-Gut. The present study was divided into three parts. In Part I the absorption of 10 and 20 microM of both (+) and (-)-terbutaline enantiomers was studied. The influence of D-glucose (80 mM) on the net fluid transport across the intestinal wall and the effective intestinal permeability (Peff) of both (+/-)-terbutaline (10 microM) and antipyrine (0.5 mM) was investigated in Part II. The experimental design of Part III was similar to that in Part II, with the exception that the perfusion solution was hypotonic and had a D-glucose concentration of 80 mM. No statistical differences were found in the Peff between terbutaline enantiomers or their concentrations. D-glucose (80 mM) did neither affect net fluid transport nor the Peff of (+/-)-terbutaline and antipyrine in the human jejunum. In contrast, hypotonic D-glucose (80 mM) solution induced a net fluid absorption (p < 0.01). In parallel with this observation, the Peff -value of (+/-)-terbutaline was unchanged, whereas the absorption of antipyrine was found to be significantly increased (p < 0.05). The increased permeability of antipyrine during the net fluid absorption phase might be due to convective paracellular flow, but more likely is it a consequence of a higher concentration gradient of the drug close to the intestinal wall, and thereby increased transcellular absorption. Based on these findings we propose that the major route for the oral absorption of terbutaline and antipyrine might be passive transcellular diffusion.