Inhalation of macrolides: a novel approach to treatment of pulmonary infections.

Systemic antibiotic treatment is established for many pulmonary diseases, e.g., cystic fibrosis (CF), bronchiectasis and chronic obstructive pulmonary disease (COPD) where recurrent bacterial infections cause a progressive decline in lung function. In the last decades inhalative administration of antibiotics was introduced into clinical routine, especially tobramycin, colistin, and aztreonam for treatment of CF and bronchiectasis. Even though they are important in systemic treatment of these diseases due to their antimicrobial spectrum and anti-inflammatory and immunomodulatory properties, macrolides (e.g., azithromycin, clarithromycin, erythromycin, and telithromycin) up to now are not administered by inhalation. The number of in vitro aerosol studies and in vivo inhalation studies is also sparse. We analyzed publications on preparation and administration of macrolide aerosols available in PUBMED focusing on recent publications. Studies with solutions and dry powder aerosols were published. Publications investigating physicochemical properties of aerosols demonstrated that macrolide aerosols may serve for inhalation and will achieve sufficient lung deposition and that the bitter taste can be masked. In vivo studies in rats demonstrated high concentrations and areas under the curve sufficient for antimicrobial treatment in alveolar macrophages and epithelial lining fluid without lung toxicity. The obtained data demonstrate the feasibility of macrolide inhalation which should be further investigated.

Inhaler competence in asthma: common errors, barriers to use and recommended solutions.

Whilst the inhaled route is the first line administration method in the management of asthma, it is well documented that patients can have problems adopting the correct inhaler technique and thus receiving adequate medication. This applies equally to metered dose inhalers and dry powder inhalers and leads to poor disease control and increased healthcare costs. Reviews have highlighted these problems and the recent European Consensus Statement developed a call to action to seek solutions. This review takes forward the challenge of inhaler competence by highlighting the issues and suggesting potential solutions to these problems. The opportunity for technological innovation and educational interventions to reduce errors is highlighted, as well as the specific challenges faced by children. This review is intended as a policy document, as most issues faced by patients have not changed for half a century, and this situation should not be allowed to continue any longer. Future direction with respect to research, policy needs and practice, together with education requirements in inhaler technique are described.

Treatment of systemic diseases by inhalation of biomolecule aerosols.

Clinical experience since many years has shown that aerosol inhalation is an established route for the treatment of pulmonary diseases. In contrast, treatment of systemic diseases by means of aerosol inhalation is a novel therapeutic approach. This was caused for a long time by a lack of accuracy, efficiency, and reproducibility of the administered drug doses due to a poor knowledge of the physiological background of aerosol inhalation, an insufficient inhaler technology as well as a suboptimal breathing procedure. However, these problems have been solved in the last years and nowadays modern aerosol delivery systems allow the production of an aerosol with a defined and optimised particle size combined with an optimized breathing maneuver and optimization of the efficacy of the technology. Clinical studies demonstrated that only a small number of morphological factors (e.g., exogen allergic alveolitis, active sarcoidosis, active smoking) influence alveolar drug deposition and the inhaled systematically active compounds caused no relevant allergic reactions even after inhalation for longer time periods. Up to now, most data are available for the inhalation of insulin which has been introduced in clinical treatment for a short time. However, a lot of other molecules have been tested in aerosol inhalation studies. This review describes some examples other than insulin in the field of inhalant treatment of systemic diseases.

Novel devices for individualized controlled inhalation can optimize aerosol therapy in efficacy, patient care and power of clinical trials.

In the treatment of pulmonary diseases the inhalation of aerosols plays a key role - it is the preferred route of drug delivery in asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. But, in contrast to oral and intravenous administration drug delivery to the lungs is controlled by additional parameters. Beside its pharmacology the active agent is furthermore determined by its aerosol characteristics as particle diameter, particle density, hygroscopicity and electrical charge. The patient related factors like age and stage of pulmonary disease will be additionally affected by the individual breathing pattern and morphometry of the lower airways. A number of these parameters with essential impact on the pulmonary drug deposition can be influenced by the performance of the inhalation system. Therefore, the optimization of nebulisation technology was a major part of aerosol science in the last decade. At this time the control of inspiration volume and air flow as well as the administration of a defined aerosol bolus was in the main focus. Up to date a more efficient and a more targeted pulmonary drug deposition - e.g., in the alveoli - will be provided by novel devices which also allow shorter treatment times and a better reproducibility of the administered lung doses. By such means of precise dosing and drug targeting the efficacy of inhalation therapy can be upgraded, e.g., the continuous inhalation of budesonide in asthma. From a patients' perspective an optimized inhalation manoeuvre means less side effects, e.g., in cystic fibrosis therapy the reduced oropharyngeal tobramycin exposure causes fewer bronchial irritations. Respecting to shorter treatment times also, this result in an improved quality of life and compliance. For clinical trials the scaling down of dose variability in combination with enhanced pulmonary deposition reduces the number of patients to be included and the requirement of pharmaceutical compounds. This review summarises principles and advances of individualised controlled inhalation (ICI) as offered by the AKITA inhalation system.

Particle clearance from the airways of subjects with bronchial hyperresponsiveness and with chronic obstructive pulmonary disease.

The aim of this study was to determine particle clearance and retention from non-alveolated airways of 14 healthy subjects (HS), 10 subjects with asymptomatic bronchial hyperresponsiveness (BHR), and 23 patients with chronic obstructive pulmonary disease (COPD). Monodisperse iron oxide particles of 1.6 micro m geometric and 3.5 micro m aerodynamic diameter labeled with (99m)Tc were delivered to the airways by inspiration of small aerosol boli into shallow volumetric lung depths. In each subject the penetration front depth of the aerosol boli was adjusted to 55% of the Fowler dead space of the airways. Particle deposition was enhanced by about 7 seconds of breath-holding after bolus inhalation. Retention of the particles in the airways during the 48 hours after their administration was assessed by measuring the decline in lung activity with a sensitive gamma counter. Particle deposition was not significantly different among study groups. Twenty-four hour particle retention in the airways was not different among study groups. Sixty-one percent of the particles were retained at 24 hours in HS, 58% in BHR, and 64% in COPD. However, subjects with BHR showed accelerated mucociliary clearance compared to healthy subjects, whereas clearance was retarded in COPD patients. This long-term particle retention in the airways has to be taken into account in aerosol toxicology risk assessment and aerosol therapy dose evaluation.

[Perspectives in the inhalative administration of drugs]. / Perspektiven in der Inhalationstherapie.

Administration of drugs via the inhalation route will find new indications in the therapy for lung diseases. Furthermore, aerosolised drugs are of increasing interest for systemic treatment. The inhalation of antibiotics is already a well established therapy in cystic fibrosis. In bronchiectasis, severe COPD with bacterial airway colonisation and in mechanically ventilated patients, aerosolised aminoglycosides may provide benefit. Substitution of alpha1-antitrypsin in lung emphysema via inhalation seems to be superior to the intravenous administration. Inhaled insulin has currently been withdrawn from the market in spite of being approved by FDA and EMEA. However, intensive scientific research is still ongoing and many clinical studies are underway in the field of the inhalation of insulin, heparins and other systemic treatments.

Systemic treatment by inhalation of macromolecules--principles, problems, and examples.

Aerosol inhalation is an established route of medical administration for the treatment of pulmonary diseases. In contrast, aerosol inhalation for treatment of systemic diseases is a novel therapeutic approach. Clinical use of the latter therapy for many years has been limited by the lack of accuracy, efficiency, and reproducibility of the administered doses. Usually, only a small fraction of inhaled drug reached the target region within the lungs. Further problems were the risk of potential allergic reactions in the respiratory tract and a potential variability of drug absorption from the alveoli into the circulation. These problems have been solved in the last years by modern aerosol delivery systems allowing the production of an aerosol with a defined and optimised aerosol particle size combined with an optimized breathing maneuver and optimization of the efficacy of the technology. Furthermore, there were no observations of relevant allergic reactions after inhalation of systemically active drugs in numerous studies. Studies demonstrated that only a small number of morphological factors influence alveolar drug deposition (e.g., exogen allergic alveolitis, active sarcoidosis, active smoking). In consequence, an increasing number of studies investigated the systemic effect of inhaled high molecular weight substances (e.g., insulin, heparin, interleukin-2) and demonstrated that controlled aerosol therapy may serve as a non-invasive alternative for drug application by means of a syringe. Our review briefly summarizes the mechanisms for pulmonary absorption of macromolecules and gives an overview on prior research in the field of inhalant treatment of systemic diseases.

Inhaled insulin--does it become reality?

After more than 80 years of history the American and European Drug Agencies (FDA and EMEA) approved the first pulmonary delivered version of insulin (Exubera) from Pfizer/Nektar early 2006. However, in October 2007, Pfizer announced it would be taking Exubera off the market, citing that the drug had failed to gain market acceptance. Since 1924 various attempts have been made to get away from injectable insulin. Three alternative delivery methods where always discussed: Delivery to the upper nasal airways or the deep lungs, and through the stomach. From these, the delivery through the deep lungs is the most promising, because the physiological barriers for the uptake are the smallest, the inspired aerosol is deposited on a large area and the absorption into the blood happens through the extremely thin alveolar membrane. However, there is concern about the long-term effects of inhaling a growth protein into the lungs. It was assumed that the large surface area over which the insulin is spread out would minimize negative effects. But recent news indicates that, at least in smokers, the bronchial tumour rate under inhaled insulin seems to be increased. These findings, despite the fact that they are not yet statistical significant and in no case found in a non-smoker, give additional arguments to stop marketing this approach. Several companies worked on providing inhalable insulin and the insulin powder inhalation system Exubera was the most advanced technology. Treatment has been approved for adults only and patients with pulmonary diseases (e.g., asthma, emphysema, COPD) and smokers (current smokers and individuals who recently quitted smoking) were excluded from this therapy. Pharmacokinetics and pharmacodynamics of Exubera are similar to those found with short-acting subcutaneous human insulin or insulin analogs. It is thus possible to use Exubera as a substitute for short-acting human insulin or insulin analogs. Typical side effects of inhaled insulin were coughing, shortness of breath, sore throat and dry mouth. Physical exercise increases the transport of inhaled insulin into the circulation and in consequence the likelihood of hypoglycemia. Other problems were the inability to deliver precise insulin doses, because the smallest blister pack available contained the equivalent of 3 U of regular insulin and this dose would make it difficult for many people using insulin to achieve accurate control, which is the real goal of any insulin therapy. For example, someone on 60 U of insulin per day would lower the blood glucose about 90 mg/dl (5 mmol) per 3 U pack, while someone on 30 U a day would drop 180 mg/dl (10 mmol) per pack. Precise control was not possible, especially compared with an insulin pump that can deliver one twentieth of a unit with precision. Another disadvantage was the size of the device. The Exubera inhaler, when closed, was about the size of a 200 ml water glass. It opened to about twice the size for delivery. To our information also other companies (Eli Lilly in cooperation with ALKERMES, Novo Nordisk (AERx, Liquid), Andaris (Powder)) stopped further development and it is unclear whether an inhaled form of insulin will ever be marketed, because of the problems that have occurred. Only Mannkind (Technosphere, Powder) is still working on a Phase III trial. However, our review will briefly summarize the experience regarding inhalant administration of insulin and will describe potential future developments for this type of therapy focussing on the lung.

Anticoagulative effects of the inhaled low molecular weight heparin certoparin in healthy subjects.

Inhalation of heparin results in local antiinflammatory and antifibrotic effects and an inhibition of blood coagulation. A number of experimental and clinical studies demonstrated that inhalant administration of heparin or low molecular weight heparin (LMWH) is a feasible and save tool for anticoagulative treatment. However, heparin and LMWH differ in respect to their molecular weight, pulmonary absorption, and principle of their anticoagulative pattern. In our study we investigated the anticoagulative effect of different doses of the LMWH certoparin after inhalation (3000 IU-9000 IU) and subcutaneous injection (3000 IU) in healthy individuals in a cross-over design. Inhalations were performed using a new device allowing inhalations with optimized and standardized breathing patterns. The anticoagulative effect was determined by measurement of the anti-factor-Xa (anti-FXa) activity. Lung function parameters were measured before and after drug inhalation. Analysis of the anti-FXa activity as a function of the time after administration revealed values of the area under the curve (AUC) of 5.70+/-1.58 U.hour/ml and 8.43+/-1.31 U.hour/ml (mean+/-SD) with interindividual coefficients of variation of 28% and 13% after injection of 3000 IU and inhalation of 9000 IU, respectively. The AUC after inhalation of 9000 IU was significantly higher (P=0.0007) compared with subcutaneous injection of 3000 IU. In consequence, in order to obtain plasma anti-FXa activities of above 0.2 U/ml, which is considered sufficient for prophylaxis of venous thrombosis, 9000 IU LMWH have to be inhaled. Compared with the subcutaneous administration, the action of certoparin is longer after inhalation than after injection. Apparently, the drug is released rapidly according to a two-compartment kinetics, and its anticoagulant activity lasts over a long time without a marked plasma peak after administration. In detail, an elevation of plasma anti-FXa activity is achieved for 12 hours to 24 hours without a distinct peak shortly after inhalation. Inhalation of LMWH does not result in any changes in lung function or other side effects. The administration of LMWH by inhalation bears the following: the non-invasive route of drug application, the low interindividual variability of the anticoagulative effect, and a long-time pharmacological effect. These properties suggest that controlled inhalation of heparin is an attractive alternative to subcutaneous administration.

Novel approaches to enhance pulmonary delivery of proteins and peptides.

In the last two decades, large efforts have been made to develop safe methods for the delivery of proteins and peptides via the lungs into blood circulation for treatment of systemic diseases. For this purpose, a number of biophysical and physiological parameters have to be considered, such as particle diameter, particle density, hygroscopicity, electrical charge, chemical properties of the substance and age, pulmonary diseases, breathing pattern, all of which affect the mechanisms of pulmonary drug deposition. Variations in these parameters result in a substantial change of particle deposition in the lung. For example, large particles (>10 microm) are not able to penetrate into the lung, because they are deposited by impaction in the upper respiratory tract. On the other hand, small particles (0.1-1.0 microm) are inspired into the alveoli but also expired without being deposited significantly. Particles of diameters 2-4 microm show the ideal pulmonary deposition behavior and are able to transport a substantial mass of pharmaceuticals into the lung. Modifications of breathing pattern allow an optimal particle deposition in the bronchial or the alveolar region. In addition, particle deposition in the alveolar region is the basis for treatment of systemic diseases by inhalant administration of drugs (e.g., insulin). This paper deals with the physical and physiological basics for inhalation therapy and demonstrates novel systems which were designed to optimize drug delivery into the lung periphery. The AKITA inhalation system is an example for a system that guides the patient through the inhalation maneuver and ensures an optimized particle deposition and a minimized intersubject variability.

Inhalation of tobramycin in patients with cystic fibrosis: comparison of two methods.

Inhalant tobramycin is established in the treatment of cystic fibrosis patients. Conventional nebulizers require a large amount of the expensive compound, because only a small fraction is deposited in the targeted lung region. In contrast, techniques based on controlled inhalation allow a high and reproducible deposition of the drug in specific lung regions. In our study we compared the efficiency of two techniques based on conventional and controlled inhalation in 16 cystic fibrosis patients aged 13-39 years. Inhalations with the doses of tobramycin of 300 mg and 150 mg were performed twice daily for three days. The efficiency of the drug deposition was measured by the determination of its serum concentration 1 h after the end of the inhalation. The mean FEV1 value in our patients was 61% of predicted, range 36%-116%. There were no differences in tobramycin serum concentrations among the three study days in both methods (controlled inhalation: 0.983 +/-0.381(+/-SD) mg/l, 1.119+/-0.448 mg/l, 1.194+/-0.568 mg/l; conventional inhalation: 1.075+/-0.798 mg/l, 1.294 0.839 mg/l and 1.269+/-0.767 mg/l, on Day 1, Day 2, and Day 3, respectively). Even though the drug amount was double in the conventional technique, there was no significant difference in its overall serum concentration from the three study days (conventional inhalation: 1.210+/-0.783 mg/l, controlled inhalation: 1.092+/-0.461 mg/l). In addition, the coefficient of variation and the required inhalation time were shorter in controlled inhalation than in conventional inhalation (42% vs. 65% and 7-8 min vs. 20 min, respectively). Our data suggest that controlled inhalation can significantly reduce the amount of a drug required for therapy, the inhalation time required for drug deposition, and the variability of pulmonary dosage. It seems probable that controlled inhalation can improve the antibiotic prevention of pulmonary infection.

[Comparison of unspecific bronchial provocation during controlled and spontaneous inhalation]. / Vergleich der unspezifischen bronchialen Provokation mit Methacholin unter kontrollierter und freier Inhalation.

Using controlled breathing patterns during inhalation of drugs is characterized by a high dose reproducibility which may be of advantage for bronchial provocation testing. In this study 30 healthy subjects with an anamnesis of atopy underwent in a randomized cross-over design bronchial provocation testing with methacholine either with the Viasys-Jäger-APS system or with controlled inhalations (AKITA-System) (controlled inhalation volume and flow). Measured was the frequency of positive test results. Positive test results were defined by a 20 % decline of FEV (1) or a 100 % increase of specific airway resistance (sRaw). There were no significant differences in the prevalence of positive test results obtained with both techniques: APS-FEV (1) : 8, AKITA-FEV (1) : 9; APS-sRaw: 18, AKITA-sRaw: 17. More subjects showed a 100 % increase of sRaw as compared to a 20 % decrease of FEV (1), which may be interesting in order to understand differences in the diagnostic information given by both parameters. However, there were some discrepancies: only in 25 of 30 cases (sRaw: 21 of 30 cases) the results (positive or negative) agreed between both techniques. Although the two techniques for bronchial provocation test showed some discrepancies, these data suggest that controlled inhalations may be an alternative to the APS-system.

Optimum peripheral drug deposition in patients with cystic fibrosis.

In order to identify the optimum particle size and breathing pattern for high peripheral deposition of inhaled drugs in patients with cystic fibrosis, regional deposition in these patients was studied systematically as a function of particle size, inhalation volume and flow rate. Regional deposition was assessed using the single-breath regional deposition technique in which the concentration profile of inhaled and exhaled non-radioactive, monodisperse test particles is analyzed. Using this technique particle deposition within the functional dead space volume and peripherally can be assessed. Regional deposition was measured in 12 patients with cystic fibrosis using 2, 3, 4, and 5.5 microm particles, inhalation volumes of 500, 1000, 1500, and 2000 cm(3), and inhalation flow rates of 100, 250, 500, and 750 cm(3)/sec. Peripheral deposition was highest when 2-3-microm particles were inhaled with air-flow rates of 250-500 cm(3)/sec. With these parameters peripheral deposition increased with increasing inhalation volume and reached values of about 60% of the total drug inhaled. It has been shown that high peripheral drug deposition can be achieved in patients with CF when inhalations are performed using an optimized combination of particle size and breathing pattern.

[Inhaled antibiotic therapy in bronchiectasis?]. / Antimikrobielle Aerosoltherapie bei Bronchiektasen?

Antimicrobial therapy is an important aspect of disease management for patients with bronchiectasis. Delivery of an inhaled antibiotic is an appealing alternative to oral or intravenous administration because the antibiotic is delivered in high concentrations directly to the site of infection, eliminating the need for high systemic concentrations and reducing the risk of systemic toxicity. In recent controlled studies these potential benefits have been assessed in patients with bronchiectasis who became colonized by P. aeruginosa and the results support the use of nebulized antibiotics. In up to one-third of patients P. aeruginosa was eradicated from their sputum by inhaled antibiotic therapy and up to 62 % of patients showed improved medical condition. The further development of new aerosol devices supported by clinical testing will allow effective management of patients with bronchiectasis by an inhalation therapy that minimizes time constraints and drug loss which may improve health status and quality of life.

Deposition of Foradil P in human lungs: comparison of in vitro and in vivo data.

In order to characterize the efficacy of dry powder inhalers, in vitro measurements are much easier to perform than human deposition studies, especially in early stages of drug development. In this study, lung deposition and delivered dose of radiolabeled Foradil P inhaled with the Aerolizer were measured in 10 healthy subjects. These data were then compared with data derived from an in vitro assessment of the device output and particle size distribution combined with mathematical modeling of lung deposition (modified ICRP-model). Delivered dose and lung deposition increased slightly but statistically significant with the inhalation peak flow in both the in vivo data and the in vitro data. The delivered dose ranged from 60% to 80% and lung deposition, relative to the fill weight, from 13% to 28%. Differences between the in vitro and in vivo data were slight and statistically not significant. This study indicates that in vitro assessment of device performance, in combination with lung deposition delivery data, are in good agreement with deposition data measured in healthy subjects. Since there was only a slight flow rate dependency of lung deposition without clinical relevance, it may additionally be concluded that the Aerolizer is a robust, easy to handle inhalation device with stable and reproducible drug delivery characteristics.

[Controlled inhalation of beta2-sympaticomimetica after bronchial provocation]. / Kontrollierte Inhalation von beta.

The results of several studies indicate that controlling the breathing pattern (inhaled volume and flow rate) during inhalation increases the efficacy of drug delivery to the lungs. By inhaling slowly, deeply and under controlled conditions, intrapulmonary deposition of aerosol and its reproducibility can be increased. However, it has not yet been proven that such inhalations are well tolerated by patients, especially those with airway obstructions. In this study 12 patients with mild asthma underwent a bronchial provocation test. The following broncholysis was performed with controlled, slow, and deep inhalation using the AKITA-device. The patients were asked about the convenience of this inhalation using a questionnaire. In 80 % the controlled inhalation was judged as convenient, neither as too slow nor as too fast, neither as too deep nor as too shallow. Thus it turned out that controlled deep and slow inhalations are convenient even for patients with mild airway obstruction.

Peripheral deposition of alpha1-protease inhibitor using commercial inhalation devices.

Patients with hereditary alpha1-proteinase inhibitor (alpha1-PI) deficiency are at risk of developing lung emphysema. To prevent the development of this disease, alpha1-PI replacement therapy via inhalation may be a more convenient and effective therapy than the intravenous administration of the drug. In order to optimise this treatment approach, lung deposition of inhaled radiolabelled alpha1-PI (Prolastin) was studied using four different commercial inhalation devices (PARI-LC Star, HaloLite, and AKITA system in combination with LC Star and Sidestream) in six patients with alpha1-PI deficiency and mild-to-severe chronic obstructive pulmonary disease. The time required to deposit 50 mg of the Prolastin (5% solution) in the lung periphery was used as a measure for the efficiency of delivery. The time was calculated from measurements of total and peripheral lung deposition of the radiolabelled alpha1-PI. This time was shortest for the AKITA system (18-24 min) and significantly higher for the PARI-LC Star (44 min) and the HaloLite (100 min). The higher efficiency of drug delivery using the AKITA system is due to the fact that this device controls breathing patterns, which are optimised for each patient individually.

Can aerosol-derived airway morphometry detect early, asymptomatical lung emphysema?

The aerosol-derived airway morphometry technique (ADAM) can be used to assess non-invasively peripheral airspace dimensions. It has been shown that this technique can identify permanent peripheral airspace enlargement in patients with lung emphysema, but it is yet unknown if early stages of emphysema can be detected. In this study, 89 aluminum welders were investigated. Although all (except two subjects) showed normal spirometry, in 29% of the subjects visual signs of early emphysema were observed with high-resolution computed tomography (HRCT) in a previous study. Using the ADAM technique, 28% of the subjects showed increased peripheral airspace dimensions. However, both groups with positive findings overlapped only in about half of the cases. Peripheral airspace dimensions correlated significantly with the mean lung density calculated from the HRCT scans, and lung density was significantly decreased in the group with increased airspace dimensions. The poor overlap of the positive findings observed with both techniques can be explained if it is considered that the visual HRCT technique and ADAM focus on different aspects of emphysematous changes in the lungs. Whereas visual HRCT is a powerful tool to identify focal changes in lung density but cannot detect mild homogeneous emphysema, ADAM delivers a measure for homogeneously distributed emphysema but cannot detect focal emphysema or regions with emphysema which are badly ventilated. Since ADAM is easy to perform, non-invasive, and can be repeatedly applied to human subjects without radiological concerns, this technique might become a useful tool for the detection and monitoring of lung emphysema in occupational medicine, epidemiology, and pharmaceutics.

[Difficulties in controlled inhalation of alpha 1-protease inhibitor]. / Neue Strategien zur kontrollierten Inhalation von alpha 1-Antitrypsin.

In this paper a number of studies will be summarized which were designed to improve the inhalation of alpha 1 -protease inhibitor in patients with alpha 1-protease inhibitor deficiency. A pilot study has shown that the high inter-individual variability of drug deposition in the lungs is due to heterogeneous breathing patterns of the patients. Controlling the breathing pattern led to a significantly decreased variability. Then it was studied which particle size and breathing pattern resulted in highest peripheral lung deposition in patients with emphysema. It was found that for 3 - 4 microm particles and slow inhalation flow rate the peripheral deposition increases with increasing inhalation volume. After the development of an inhalation device which allows to perform controlled inhalations in clinical practice it was shown that this device, in combination with a breathing pattern individually normalized to the patients lung function, allows to deposit nearly 60 % of the drug into the patients lung periphery.