Value through Innovation01 August 2014

Scientific Publications

Boehringer Ingelheim offers an overview of scientific publications on the following pages. This overview represents all publications of the last three years (YTD) where employees of Boehringer Ingelheim worldwide were involved.

65 publications regarding New Technologies
  • Author:
    Ciciliani A M; Langguth P; Bickmann D; Wachtel H; Voshaar T
    Title:
    In Vitro Dosisvergleich des Respimat® Soft Inhaler. mit Trockenpulverinhalatoren für die COPD-Therapie
    Source:
    DGP-Kongress, Mar 27, 2014
  • Author:
    Cirillo P
    Source:
    6. Fachtagung Kunststoffe Medical, Wuerzburg (Germany), May 8-9, 2012.
  • Author:
    Norwood DL; Mulis JO; Feinberg TN; Davis LK
    Title:
    N-nitrosamines as "special case" leachables in a metered dose inhaler drug product.
    Source:
    PDA J Pharm Sci Technol 63 (4), 307-321 (2009)
    Abstract:
    N-nitrosamines are chemical entities, some of which are considered to be possible human carcinogens, which can be found at trace levels in some types of foods, tobacco smoke, certain cosmetics, and certain types of rubber. N-nitrosamines are of regulatory concern as leachables in inhalation drug products, particularly metered dose inhalers, which incorporate rubber seals into their container closure systems. The United States Food and Drug Administration considers N-nitrosamines (along with polycyclic aromatic hydrocarbons and 2-mercaptobenzothiazole) to be "special case" leachables in inhalation drug products, meaning that there are no recognized safety or analytical thresholds and these compounds must therefore be identified and quantitated at the lowest practical level. This report presents the development of a quantitative analytical method for target volatile N-nitrosamines in a metered dose inhaler drug product, Atrovent.RTM. HFA. The method incorporates a target analyte recovery procedure from the drug product matrix with analysis by gas chromatography/thermal energy analysis detection. The capability of the method was investigated with respect to specificity, linearity/range, accuracy (linearity of recovery), precision (repeatability, intermediate precision), limits of quantitation, standard/sample stability, and system suitability. Sample analyses showed that Atrovent.RTM. HFA contains no target N-nitrosamines at the trace level of 1 ng/canister.
  • Author:
    Golberg Ch; Zumblick O; Wachtel H
    Title:
    Development of a combination measuring system to simultaneously characterize spraytime and fine particle fraction (FPD) of Respimat inhaler.
    Source:
    Respiratory Drug Delivery 2010 Conference, Orlando (United States), Apr 25-29, 2010.
  • Author:
    Zumblick O; Golberg Ch; Moser A; Weiland F; Kunze H
    Title:
    Quality by design (QbD) based on the analysis of critical quality attributes (CQAs) of the Respimat noozle.
    Source:
    Respiratory Drug Delivery 2010 Conference, Orlando (United States), Apr 25-29, 2010.
  • Author:
    Aven M
    Title:
    Applying elements of quality by design to optimize the aerosol properties of Spiriva Respimat.
    Source:
    Respiratory Drug Delivery, Scottsdale (United States), May 11-15, 2008.
  • Author:
    Wachtel H
    Title:
    Aerodynamic optimization of HandiHaler and Respimat: The roles of computational fluid dynamics and flow visualization.
    Source:
    Respiratory Drug Delivery, Scottsdale (United States), May 11-15, 2008.
  • Author:
    Aven M
    Title:
    Analytical methods applied in the development and quality control of the Respimat Soft Mist Inhaler.
    Source:
    International Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology 2004. - Nuernberg, 2004. - P. 725-726 Proceedings of the International Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, Nuernberg (Germany), Mar 15-18, 2004.
  • Author:
    Krackhardt D; Stanko C; Wachtel H; Kamin W
    Title:
    The Respimat in use with children - An evulation based on breathing patterns.
    Source:
    16th ISAM (International Society for Aerosols in Medicine) Congress, Tours (France), Jun 16-20, 2007.
  • Author:
    Hochrainer D; Hoelz H; Kreher C; Scaffidi L; Spallek M; Wachtel H
    Title:
    Comparison of the aerosol velocity and spray duration of respimat(R) soft misttrade mark inhaler and pressurized metered dose inhaler.
    Source:
    J Aerosol Med 18 (3), 273-282 (2005)
    Abstract:
    Apart from particle size distribution, spray velocity is one of the most important aerosol characteristics that influence lung deposition of inhaled drugs. The time period over which the aerosol is released (spray duration) is also important for coordination of inhalation. Respimat (R) Soft Misttrade mark Inhaler (SMI) is a new generation, propellant-free inhaler that delivers drug to the lung much more efficiently than pressurised metered dose inhalers (pMDIs). The objective of this study was to compare the velocity and spray duration of aerosol clouds produced by Respimat(R) SMI with those from a variety of chlorofluorocarbon (CFC) and hydrofluoroalkane (HFA) pMDIs. All inhalers contained solutions or suspensions of bronchodilators. A videorecording method was used to determine the aerosol velocity. For spray duration, the time for generation of the Soft Misttrade mark by Respimat(R) SMI was initially determined using three different methods (videorecording [techniques A and B], laser light diffraction and rotating disc). Videorecording was then used to compare the spray duration of Respimat(R) SMI with those from the other inhalers. The Soft Misttrade mark produced by Respimat(R) SMI moved much more slowly and had a more prolonged duration than aerosol clouds from pMDIs (mean velocity at a 10-cm distance from the nozzle: Respimat(R) SMI, 0.8 m/sec; pMDIs, 2.0-8.4 m/sec; mean duration: Respimat(R) SMI, 1.5 sec; pMDIs, 0.15-0.36 sec). These characteristics should result in improved lung and reduced oropharyngeal deposition, and are likely to simplify coordination of inhaler actuation and inhalation compared with pMDIs.
  • Author:
    Dalby R; Spallek M; Voshaar T
    Title:
    A review of the development of Respimat Soft Mist Inhaler.
    Source:
    Int J Pharm 283 (1-2), 1-9 (2004)
    Abstract:
    Respimat(R) Soft Mist[TM] Inhaler (SMI) is a new generation inhaler from Boehringer Ingelheim developed for use with respiratory drugs. The device functions by forcing a metered dose of drug solution through a unique and precisely engineered nozzle (the uniblock), producing two fine jets of liquid that converge at a pre-set angle. The collision of these two jets generates the soft mist. The soft mist contains a high fine particle fraction of approximately 65 to 80%. This is higher than aerosol clouds from conventional portable inhaler devices, such as pressurised metered dose inhalers (pMDIs) and dry powder inhalers (DPIs). In addition, the relatively long generation time of the aerosol cloud (approximately 1.5 s) facilitates co-ordination of inhalation and actuation - a major problem with pMDIs. These features, together with the slow velocity of the soft mist, result in larger amounts of the drug reaching the lungs and less being deposited in the oropharynx compared with either pMDIs or DPIs. Generation of the soft mist from Respimat(R) SMI is purely mechanical, so propellants are not necessary. The innovative design of Respimat(R) SMI, using water-based drug formulations, ensures patients receive consistent and reliable doses of the drug with each actuation. The device was initially tested in scintigraphic lung deposition studies and produced encouraging results when compared with the chlorofluorocarbon-based pMDI (CFC-MDI). Subsequent clinical studies have confirmed that Respimat(R) SMI is effective and safe in delivering bronchodilators to patients with asthma or chronic obstructive pulmonary disease.
  • Author:
    Kilfeather SA; Ponitz HH; Beck E; Schmidt P; Lee A; Bowen I; Hesse C
    Title:
    Improved delivery of ipratropium bromide/fenoterol from Respimat (R) Soft Mist (TM) Inhaler in patients with COPD.
    Source:
    Respir Med 98 (5), 387-397 (2004)
    Abstract:
    We performed a multicentre, randomised, double-blind (within-device), placebo- and active-controlled, parallel-group study to compare the efficacy and safety of ipratropium bromide plus fenoterol hydrobromide (IB/FEN; Berodual(R)) delivered via the novel, propellant-free Respimat(R) Soft Mist(TM) Inhaler (SMI) and from a chlorofluorocarbon (CFC)-metered-dose inhaler (MDI) in moderate-to-severe chronic obstructive pulmonary disease (COPD) patients. After 2-weeks' run-in (CFC-MDI [IB 20 mug/FEN 50 mug per actuation] two actuations q.i.d. [MDI 40/100]), 892 patients were randomised to Respimat(R) SMI containing IB 10 mug/FEN 25 mug (Respimat(R) SMI 10/25), IB 20 mug/FEN 50 mug (Respimat(R) SMI 20/50) or placebo (one actuation q.i.d.), or a CFC-MDI containing IB 20 mug/FEN 50 mug (MDI 40/100) or placebo (two actuations q.i.d.) for 12 weeks. Analysis of the primary endpoint (change in forced expiratory volume in 1 s [FEV1] in the first 60 min after dosing [area under the curve; AUC(0-1h)]) on day 85 showed that the efficacy of Respimat(R) SMI 20/50 (but not Respimat(R) SMI 10/25) was not inferior to that of MDI 40/100. The safety profile of Respimat(R) SMI was comparable to CFC-MDI. Switching from MDI 40/100 to Respimat(R) SMI was well tolerated. Respimat(R) SMI enables a 50% reduction of the nominal inhaled dose of IB/FEN in COPD patients white offering similar therapeutic efficacy and safety to the CFC-MDI.
  • Author:
    Boeck G
    Title:
    Respimat soft mist inhaler - designed to meet the ideal
    Source:
    in: Scheuch G (Ed.): Aerosole in der Inhalationstherapie VIII. - Muenchen : Dustrie, 2004. - P. 121-132.
  • Author:
    Vincken W; Bantje T; Middle MV; Gerken F; Moonen D
    Title:
    Long-term efficacy and safety of ipratropium bromide plus fenoterol via Respimat (R) Soft Mist (TM) inhaler (SMI) versus a pressurised metered-dose inhaler in asthma.
    Source:
    Clin Drug Invest 24 (1), 17-28 (2004)
    Abstract:
    Objective: Respimat(R) Soft Mist(TM) Inhaler (SMI) is a novel, propellant-free device that significantly increases lung deposition compared with pressurised metered-dose inhalers (pMDIs). The aim of this study was to compare the efficacy and safety of ipratropium bromide/fenoterol hydrobromide (IB/FEN; Berodual(R)) delivered via Respimat(R) SMI and via a chlorofluorocarbon (CFC)-driven pMDI (CFC-MDI) in patients with asthma. Design: Multicentre, randomised, double-blind, placebo-controlled, parallel-group study. Patients: 631 patients (18-65 years old) with stable asthma. Interventions: After a 2-week run-in period (IB/FEN 20 mug/50 mug via CFC-MDI, two actuations four times a day), patients were randomised to 12 weeks' treatment with one of five treatments: IB/FEN 10 mug/25 mug, 20 mug/50 mug or placebo via Respimat(R) SMI (one actuation four times a day), or IB/FEN 20 mug/50 mug or placebo via CFC-MDI (two actuations four times a day). The main efficacy measure was lung function (assessed on days 1, 29, 57 and 85); safety was assessed by monitoring adverse events. Results: Bronchodilator responses to IB/FEN were much greater than those to placebo (mean peak increases in forced expiratory volume in 1 second [FEV1] on day 85: 0.498-0.521 L, active treatment; 0.215 and 0.240 L, placebo). According to the primary endpoint, i.e. the average change in FEV1 from test-day baseline over the 6 hours after dosing on day 85, neither IB/FEN dosage via Respimat(R) SMI was inferior to IB/FEN via pMDI (p < 0.001). Non-inferiority of the two Respimat(R) SMI dosages was supported by analyses of other lung function measures, e.g. average change in FEV1 from test-day baseline over the 6 hours after dosing on the other 3 test days, and peak FEV1 on all test days. Overall, the safety profile of IB/FEN via Respimat(R) SMI was comparable to that via CFC-MDI. Conclusion: IB/FEN from Respimat(R) SMI is as effective and safe as from CFC-MDI and enables a 2- to 4-fold daily dose reduction of IB/FEN. DERWENT-Abstract. Methods 631 Adult patients (17-79 yr old) with stable asthma were included. After a 2-wk run-in period (IB/FEN 20 ug/50 ug via CFC-MDI, 2 actuations q.i.d.), patients were randomized to 12 wk treatment with 1 of 5 treatments: IB/FEN 10 ug/25 ug, 20 ug/50 ug or placebo via Respimat SMI (1 actuation q.i.d.), or IB/FEN 20 ug/50 ug or placebo via CFC-MDI (2 actuations q.i.d.). The main efficacy measure was lung function (assessed on days 1, 29, 57 and 85). Results Bronchodilator responses to IB/FEN were much greater than those to placebo (mean peak increases in FEV1 on day 85: 0.498-0.521 L, active treatment; 0.215 and 0.240 L, placebo). According to the primary endpoint, i.e. the average change in FEV1 from test-day baseline over the 6 hr after dosing on day 85, neither IB/FEN dosage via Respimat SMI was inferior to IB/FEN via pMDI. Non-inferiority of the 2 Respimat SMI dosages was supported by analyses of other lung function measures, e.g. average change in FEV1 from test-day baseline over the 6 hr after dosing on the other 3 test days, and peak FEV1 on all test days. Overall, the safety profile of IB/FEN via Respimat SMI was comparable to that via CFC-MDI. Adverse events included asthma exacerbation, upper respiratory tract infection, headache, influenza-like symptoms, rhinitis, bronchitis, dyspnea and pharyngitis. The more serious of these were not considered to be related to the study drug.
  • Author:
    Boeck G
    Title:
    Respimat: The mild (r)evolution of aerosol- and inhalation technology.
    Source:
    Tagung fuer Krankenhausapotheker: Neue Perspektiven: Aerosoltechnologie - Kardiologie - Virologie, Bad Nauheim (Germany), Mar 5, 2004.
  • Author:
    Boeck G
    Title:
    Comparison of the marketing authorization applications respimat(R) soft mist(TM) inhaler in Europe and United States.
    Source:
    in: Scheuch G. (Ed.): Aerosole in der Inhalationstherapie VIII. - Muenchen : Dustri, 2004. - P- 133-144. Deutsches VIII. Aerosol Therapie Seminar, Marburg (Germany), Nov 14-15, 2003.
    Abstract:
    Respimat(R) Soft Mist(TM) Inhaler (SMI) is a new generation inhaler from Boehringer Ingelheim developed for use with respiratory drugs dissolved in aqueous solutions. Respimat(R) SMI is a propellant-free and active inhaler, which stores the energy, coming from a 180° turning movement of the device base, in a spring for the subsequent aerosol generation. The aqueous solution for inhalation is filled into a cartridge that is inserted into the inhaler prior to first use. This new inhaler category raised new and uncustomary regulatory challenges primarily in Europe. In Europe a Respimat(R) SMI product is regulated both as a medicinal product and as a medical device: the combination of device and cartridge is considered to be a medicinal product, the device is considered to be a medical device. This additional classification of the inhaler as a medical device significantly increased the efforts for marketing authorization.
  • Author:
    Spallek M; Geser J; Eicher J; Reinecke H
    Title:
    Scale-up and production challenges of bringing respimat soft mist inhaler (SMI) to market.
    Source:
    Respiratory Drug Delivery IX, Palm Spring (United States), Apr 26-30, 2004.
  • Author:
    Vincken W; Dewberry H; Moonen D
    Title:
    Fenoterol delivery by respimat soft mist inhaler versus CFC metered dose inhaler: cumulative dose-response study in asthma patients.
    Source:
    J Asthma 40 (6), 7721-730 (2003)
    Abstract:
    Objectives. Respimat(R) (RMT) soft mist inhaler (SMI) is a novel, propellant-free alternative to chlorofluorocarbon metered-dose inhalers (CFC-MDIs). The aim of this study was to evaluate the safety and establish the equipotent dose of fenoterol delivered by RMT SMI vs. a conventional MDI. Design. Double-blind, randomized, crossover, comparative study between fenoterol inhaled via RMT (either 50 [mu]g/actuation, RMT50; or 100 [mu]g/actuation, RMT100) and MDI (100 [mu]g/actuation; MDI100). Patients and interventions. A total of 41 asthma patients received cumulative doses of fenoterol 600 [mu]g (RMT50) or 1200 [mu]g (RMT100 and MDI100) on 3 test days. Measurements and results. The bronchodilator response (forced expiratory volume in 1 second [FEV<ovid:inf>1</ovid:inf>]) was considered therapeutically equivalent (i.e., noninferior) if the 95% confidence intervals for the difference in their mean changes from baseline were within limits of +/- 0.15 L. Systemic exposure was evaluated from plasma fenoterol levels. Adverse events (AEs) were recorded. RMT50 and RMT100 produced noninferior bronchodilatation to MDI100 from 30minutes after the first dose. RMT50 showed equivalent safety and tolerability to MDI100, whereas RMT100 produced a higher incidence of AEs, a significantly greater plasma potassium reduction and a significant increase in pulse rate. Fenoterol plasma levels were twice as high with RMT100 as with RMT50 or MDI100. Conclusions. The nominal dose of fenoterol administered via RMT SMI can be at least halved to achieve equivalent efficacy, safety, and tolerability to a MDI.
  • Author:
    Dahl R; Backer V; Ollgaard B; Gerken F; Kesten S
    Title:
    Assessment of patient performance of the HandiHaler (R) compared with the metered dose inhaler four weeks after instruction.
    Source:
    Respir Med 97 (10), 1126-1133 (2003)
    Abstract:
    The HandiHaler(R) is a novel breath-actuated dry powder system designed for the delivery of tiotropium 18mug daily in the treatment of COPD. We compared patient ability to use the HandiHaler(R) or metered dose inhaler (MDI) device correctly 4 weeks after receiving brief instructions and device demonstration. A single-blind study was conducted in COPD patients in two centers in Denmark. All patients (n = 151) received one placebo capsule via the HandiHaler(R) daily and ipratropium (20 mug) two actuations via the MDI q.i.d. Mean FEV1 for all patients was 1.25 + 0.54 (46% predicted). Twelve instructions establishing proper device use were evaluated for the MDI and Handihaler. Error scores were analyzed by number of patients with less, equal or more errors when using HandiHaler(R) compared to MDI in the total efficacy population (n = 139) and according to those who had not previously used an MDI for at least 12 months (MDI beginners) (n = 74) and those who had used an MIDI (MDI experienced) (n = 65). Four weeks after device instruction, a higher proportion of patients in the total population (P<0.01) had fewer errors with the HandiHaler(R) (35.3%) compared to the MDI (15.1%). The number of errors was equal in 50% of patients. Similar findings were observed in the subgroup of patients who were MDI beginners (42% vs. 11%, P<0.01) with nonsignificant trends in favor of the HandiHaler(R) 1 in those patients who were MDI experienced (29.7% vs. 18.9%, P = 0.096). Similar results in favor of HandiHaler(R) were noted across different age and sex strata. The proportion of patients correctly using the device on the first of three attempts was 59.7% and 54.7% for the HandiHaler(R) and MDI, respectively (P = 0.399). In summary, use of the HandiHaler(R) can be easily taught with fewer errors compared to the MDI. Furthermore, patient performance using the HandiHaler(R) was superior to that with an MDI despite prior MDI experience and more frequent usage.
  • Author:
    Hodder R; Pavia DD; Dewberry HM; Alexander KM; Lacono P; Ponitz HH; Beck E
    Title:
    Comparison of the safety relating to paradoxical bronchoconstriction of ipratropium bromide (IB) alone or combined with fenoterol hydrobromide (FEN) inhaled from a new soft mist inhaler (SMI) and from a conventional metered dose inhaler (CFC-MDI) in asthma and COPD patients
    Source:
    Annual Congress of the European Respiratory Society, Stockholm (Sweden), Sep 14-18, 2002Eur Respir J 20 (Suppl. 38), 246S P1594 (2002)
    Abstract:
    Three Phase III studies compared the safety of ipratropium bromide (IB) and IB/ fenoterol hydrobromide (FEN) (Berodual) delivered from Respimat (RMT) soft mist inhaler (SMI), a novel, propellant-free inhaler, or conventional metered dose inhaler (CFC-MDI) in 2169 patients with asthma or COPD. The most common event in all groups was an asymptomatic drop in FEV1. Only 1 asthma patient (MDI placebo (PLA)) experienced paradoxical bronchospasm. Events were more frequent in the PLA groups with both devices. Overall, for both active drug (ACT) and PLA, the incidence of respiratory events was similar for RMT SMI and CFC-MDI. Thus, these studies demonstrate the safety of RMT SMI with regard to paradoxical bronchoconstriction in patients with asthma or COPD. DERWENT-Abstract. Methods 2169 patients (1306 male, mean age 58 yr) with asthma (n=631) or COPD (n=1538) were administered ACT (n=1111) or PLA (n=251) via RMT SMI and ACT (n=551) and PLA (n=256) via CFC-MDI for up to 12 wk. Results 1886 Patients completed test-day 85. Mean baseline FEV1 was 2.17 l (66% predicted) in asthma patients and 1.09 l (41% predicted) in COPD patients; values were similar within treatment groups. The most common event in all groups was an asymptomatic FEV1 drop of at least 15%. Only 1 asthma patient (MDI PLA) experienced paradoxical bronchospasm. There was no increase in the incidence of respiratory events during 12 wk treatment. Events were more frequent in the PLA groups with both devices. Overall, for both ACT and PLA, the incidence of respiratory events was similar for RMT SMI and CFC-MDI. No cases of paradoxical bronchoconstriction were reported with RMT SMI.
  • Author:
    Boeck G
    Title:
    Respimat soft mist inhaler (SMI) - a new inhaler concept.
    Source:
    11th Annual International Conference "Portable Inhalers", London (Great Britain), Jan 27-28, 2003.
  • Author:
    Rothenberg SJ; Barnett JF; Dearlove GE; Parker RM; Ball DJ; Brady JT; Yeh HC; Greenspan BJ
    Title:
    Characterization of a microprocessor-controlled tubular multiple metered dose inhaler aerosol generator for inhalation exposures of pharmaceuticals.
    Source:
    J Aerosol Med 13 (3), 157-167 (2000)
    Abstract:
    A microprocessor-controlled tubular multiple metered dose inhaler (MDI) aerosol generator was constructed for the delivery of pharmaceutical aerosols to inhalation chambers. The MDIs were mounted in four cassettes containing one to four MDIs on a stepped end plate. The MDIs in each cassette were pneumatically activated at intervals that were controlled by the microprocessor. The cassettes permitted easy replacement of each set of MDIs with a fresh set of MDIs whenever necessary. Aerosol concentration was controlled by varying the number of active MDIs in each cassette and the frequency of activations per minute of each row. Aerosol from the MDIs flowed along the long axis of the tube, which provided a path length sufficient to diminish impaction losses. Using a light-scattering device to monitor the aerosol concentration, the pulsatile output from the MDIs in the cassettes was demonstrated to be adequately damped out provided that the dilution/mixing/aging chamber exceeded 3 ft in length. The tube diameter selected was the minimum compatible with mounting the required number of MDIs so that the linear velocity of the aerosol was adequate to efficiently transport the aerosol out of the dilution chamber. Aerosol concentration and particle size data were recorded for a nose-only rodent exposure chamber. Reproducible aerosol concentrations ranging from 0.03 to 0.6 mg/L were generated. Particle sizes ranged from 2- to 3-.mu.m mass median aerodynamic diameter. Thus, the aerosol generated was within the size range suitable for inhalation exposures.
  • Author:
    van Noord JA; Smeets JJ; Creemers JPHM; Greefhorst LPM; Dewberry H; Cornelissen PJG
    Title:
    Delivery of fenoterol via Respimat, a novel "soft mist" inhaler: A randomisd, double-blind (within device), placebo-controlled, cross-over, dose-ranging study in asthmatic patients.
    Source:
    Respiration 67 (6), 672-678 (2000)
    Abstract:
    Background: The phase-out of chlorofluorocarbons (CFCs) for metered dose inhalers (MDIs) has prompted the development of alternative propellants and the design of propellant-free devices for inhalation therapy. Objective: This study was carried out to determine the dose of fenoterol inhaled from Respimat.sup..RTM. (RMT), a new propellant-free soft mist inhaler, which is equivalent in terms of efficacy and safety to 1 puff of either 100 or 200 .mu.g fenoterol inhaled from a conventional CFC-MDI (Berotec.sup..RTM.). Methods: Sixty-two asthmatic patients (35 male, 27 female) with a mean baseline FEV.sub.1 of 1.7 liters, corresponding to 55% of the predicted normal value, were randomized at two study centers to 4 of a total of 8 possible treatments: placebo; 12.5, 25, 50, 100, or 200 .mu.g fenoterol via RMT, and 100 or 200 .mu.g fenoterol delivered via the MDI. Results: Fifty-nine patients completed the study as planned. Results of the therapeutic equivalence test for the primary endpoint, average FEV.sub.1 (AUC.sub.0.sub.-.sub.6)/6 and for the secondary endpoint, peak FEV.sub.1, showed that the 12.5- and 25-pg fenoterol doses administered via RMT were equivalent to the 100 .mu.g fenoterol dose from the MDI. The 50-, 100- and 200-.mu.g fenoterol doses delivered by RMT did not meet the criterion for therapeutic equivalence with the 100-.mu.g dose from the MDI, and if tested for a difference would have been significantly different in favor of RMT. All 5 RMT fenoterol doses were therapeutically equivalent to the MDI 200-.mu.g fenoterol dose. Headache, reported by 4 patients on test days and 2 patients between test days in those randomized to RMT, was the most common adverse event, but the active treatments were generally well tolerated with no dose-dependent increases in incidence or severity of adverse events observed. Conclusions: The results from the study suggest that safe and efficacious bronchodilation can be obtained from single-dose fenoterol administered via RMT. Use of lower absolute doses to obtain a clinically significant improvement in pulmonary function may be possible because of the increased lung deposition achievable with the novel soft mist inhaler.
  • Author:
    Goldberg J; Freund E; Beckers B; Hinzmann R
    Title:
    Improved delivery of fenoterol plus ipratropium bromide using respimat compared with a conventional metered dose inhaler.
    Source:
    Eur Respir J 17 (2), 225-232 (2001)
    Abstract:
    The efficacy and safety of Respimat (Boehr. Ingelheim) in delivering combined doses of fenoterol hydrobromide (FH) and ipratropium bromide (IB) (FF/IB) compared with a metered dose inhaler (MDI, Boehr. Ingelheim) was assessed in 62 patients with stable perennial bronchial asthma in a randomized, 5-period, cross-over study. A comparison of the average increase in FEV1 up to 6 hr (AUC0-6hr) between lowest and highest doses of FH/IB showed that bronchodilation was greater for higher dose. Inhalation via Respimat produced higher plasma and HF excretion values when compared with same doses delivered by MDI. Systemic availability of both drugs was higher following inhalation via Respimat compared with MDI. Treatments were safe with regards to vital signs and well tolerated. The administration of FH/IB via Respimat is as effective and as safe as higher doses given via a MDI. DERWENT-Abstract. Methods 62 Patients (32 males, mean age 39.3 yr) with stable bronchial asthma were randomized to receive 5/8 possible treatments: placebo, FH/IB 12.5/5, 25/10, 50/20, 100/40 or 200/80 ug delivered via Respimat and FH/IB 50/20 or 100/40 ug via MDI. Results All HF/IB treatments produced notably greater increases in FEV1 than placebo. Adjusted AUC0-6 hr following HF/IB doses of 12.5/5, 25/10, 50/20, 100/40 and 200/80 ug administered via Respimat were 0.60, 0.73, 0.90 and 1.03 l respectively compared with 0.14 l after placebo Respimat administration. A comparison of AUC0-6 hr between lowest and highest doses of FH/IB showed that bronchodilation was notably greater for the higher dose. Median time to onset of therapeutic response with each active treatment ranged from 2.3-4.6 min. Inhalation via Respimat produced higher plasma and HF excretion values when compared with same doses delivered by MDI. Following delivery of single doses of 20 or 40 ug of IB, amounts for drug excretion were higher for Respimat than MDI. There was a 2-fold greater systemic availability of both drugs following inhalation via Respimat compared with MDI. Treatments were safe and well tolerated. A total of 33 adverse events were reported and no events were reported with lowest FH/IB dose. 2/29 Patients in controls experienced paradoxical bronchoconstriction. There was 1 serious event, an asthma exacerbation due to a respiratory tract infection, which required overnight hospitalization and it was unrelated to test drug. Totally 2 patients withdrew from the study. The number of patients with clinically notable
  • Author:
    Schappert B; Koehler M; Wolf K; Fimmers R; Stechert R
    Title:
    Clinical results of a newly developed CFC-free fenoterol-containing metered dose inhaler.
    Source:
    3rd Annual Congress on Clinical Pharmacology, Cologne, Germany, 2001.Eur J Clin Pharmacol 57 (8), A24 (2001)
    Abstract:
    The safety and efficacy of a CFC-free fenoterol metered dose inhaler (Berotec-N) were studied in 2914 patients suffering from chronic obstructive respiratory tract disease. The CFC-free metered dose inhaler of fenoterol was safe and effective. The majority of patients judged the efficacy to be similar of superior to that of a CFC-containing metered dose inhaler of fenoterol (Berotec). In addition, the absolute quantity of inhaled fenoterol was reduced compared with the CFC-containing inhaler. Adverse effects were mild and transient. DERWENT-Abstract. Methods The safety and efficacy of a CFC-free 100 ug/puff fenoterol metered dose inhaler (Berotec N) were studied. 2914 Patients with chronic obstructive respiratory tract disease were treated with the CFC-free fenoterol (Berotec-N) for 3 wk. Before this, they had been treated with a CFC-containing formulation (Berotec 200 ug/puff). The majority of patients (69.5%) inhaled 1-2 puffs 100 ug fenoterol 2-3 times/day. Results Mild transient adverse effects were observed in 11 patients. All clinical parameters improved under therapy with Berotec-N without a necessity to increase co-medication. Patients did not have to increase the number of puffs per day of the 100 ug fenoterol metered dose inhaler (Berotec-N) compared to their previous Berotec 200 ug metered dose inhaler. The majority of patients judged the efficacy (95.6%) and safety (99.3%) of the CFC-free Berotec-N to be better or equivalent to those of the CFC-containing metered dose inhaler. (E83)
  • Author:
    Iacono P; Velicitat P; Guemas E; Leclerc V; Thebault JJ
    Title:
    Improved delivery of ipratropium bromide using Respimat (a new soft mist inhaler) compared with a conventional metered dose inhaler: cumulative dose response study in patients with COPD.
    Source:
    Respir Med 94 (5), 490-495 (2000)
    Abstract:
    Respimat (RMT) is a reusable, propellant-free, soft mist inhaler (SMI), a novel device for inhalation therapy. We conducted a three-period cross-over study to evaluate the safety and efficacy of cumulative doses of ipratropium bromide inhaled from RMT (Two dose levels) or from a pressurized metered dose inhaler (MDI), in 36 patients with chronic obstructive pulmonary disease (COPD). The bronchodilator effect of ipratropium bromide was greater when administered via RMT (10 or 20 microg per puff, given double-blind within device, to total doses of 160 or 320 microg) than via MDI (20 microg per puff, total dose 320 microg). The bronchodilator effects of the 160 and 320 microg doses delivered via RMT were similar. Cumulative ipratropium bromide doses of 320 microg given via MDI or RMT and 160 microg given via RMT produced similar safety profiles. Between 45 min after the first drug inhalation and 45 min after the final dose, greater bronchodilatory effect was obtained from half the cumulative dose of ipratropium (RMT 10 microg per puff) when compared with the MDI (20 microg per puff). Therefore, ipratropium bromide delivered by RMT is as safe as, and can be more effective than, the MDI on acute administration in patients with COPD.
  • Author:
    Kunkel G; Magnussen H; Bergmann KC; Juergens UR; deMay C; Freund E; Hinzmann R; Becker B
    Title:
    Respimat(R) (a new soft mist inhaler) delivering fenoterol plus ipratropium bromide provides equivalent bronchodilation at half the cumulative dose compared with a conventional metered dose inhaler in asthmatic patients.
    Source:
    Respiration 67 (3), 306-314 (2000)
    Abstract:
    Background: Respimat(R), a possible alternative to the conventional metered dose inhaler (MDI), is a novel, reusable, propellant-free, multidose soft mist inhaler. Respimat slowly releases a metered dose of active substance as a soft mist with a high proportion of the dose in the fine particle fraction, leading to improved lung deposition following inhalation when compared with the conventional MDI. Objectives and Methods: The equipotent bronchodilating efficacy and safety of a combination of fenoterol hydrobromide and ipratropium bromide (F/I) in cumulative doses delivered by either Respimat or pressurised MDI was assessed in a randomised, controlled, double-blind (within device) 4-way crossover study. Forty-three patients with stable asthma (mean FEV1 62% predicted) responsive to F/I inhaled cumulatively 16 puffs on each of 4 test days (1 + 1 + 2 + 4 + 8 puffs at 50-min intervals) via Respimat delivering 50/20, 25/20 or 25/10 mu g F/I per puff or via MDI delivering 50/20 mu g WI per puff. Results: Cumulative doses of 400/160 and 400/320 mu g F/I via Respimat produced bronchodilation (evaluated by average increase in FEV1 45-245 min after first inhalation) equivalent to that achieved with a cumulative 800/320 mu g F/I via MDI (mean increase in FEV1 above baseline 0.76, 0.73 and 0.71 litres, respectively). The tolerability of the F/I combination via Respimat was also comparable to that of twice the dose delivered via MDI. Conclusion: Therefore, a fenoterol hydrobromide/ipratropium bromide combination delivered by Respimat is as safe and effective as the MDI at half the cumulative dose, on acute administration to patients with asthma.
  • Author:
    Schmelzer Ch; Bagel S
    Title:
    Microbiological quality of respimat(R) (soft mist inhaler) cartridges after use in COPD patients and in-vitro tests.
    Source:
    Nasal and Pulmonary Drug Delivery Conf VII, Barcelona (Spain), Aug 24-26, 2001
  • Author:
    Spallek M
    Title:
    The soft mist inhaler Respimat performance a current status.
    Source:
    A NZ SRS ASM Aerosol Symposium, Brisbane (Australia), Mar 18-19, 2001
  • Author:
    Schmelzer C; Bagel S
    Title:
    Microbiological integrity of Respimat soft mist inhaler (SMI) cartridges after use in COPD patients.
    Source:
    ISAM Congress, Interlaken (Switzerland), Sep 17-21, 2001
  • Author:
    Huchon G; Hofbauer P; Cannizzaro G; Iacono P; Wald F
    Title:
    Comparison of the safety of drug delivery via HFA- and CFC-metered dose inhalers in CAO.
    Source:
    Eur Respir J 15 (4), 663-669 (2000)
    Abstract:
    The objective of this study was to compare the long-term safety of a fixed combination of fenoterol hydrobromide (50 mu g) and ipratropium bromide (20 mu g) delivered using a metered dose inhaler (MDI) formulated with a non-chlorinated propellant, hydrofluoroalkane134a (HFA-MDI), with delivery using the conventional chlorofluorocarbon propellant (CFC-MDI, Berodual(R)/Bronchodual(R)). The study was designed according to Safety Assessment of Marketed Medicines (SAMM) guidelines, to reflect as far as possible the use of MDIs under normal prescribing conditions. Two thousand and twenty-seven patients with chronic airways obstruction (CAO) were enrolled from 99 centres in France, 95 centres in Germany and 24 centres in Italy. Following a 2-week run-in period, patients were randomized on a 2:1 basis (1,348 patients to HFA-MDI, 679 patients to CFC-MDI) to receive a flexible dose regimen of the combination (2 puffs, 2-4 times a day, as prescribed by the investigator) during a 12-week open label phase. The overall incidence of adverse events was comparable between both groups, In addition, the incidence of respiratory side effects was also similar, with CAO exacerbations or bronchitis the most frequently recorded events. The safety profile of the HFA formulation was comparable to those of the marketed CFC-MDIs used in Germany and France/Italy No clinically significant differences were detected between HFA134a or CPC driven inhalers on the switch from CFC- to HFA-MDI (2 weeks before randomisation versus 2 weeks after randomization). There was a trend for taste complaints to be reported more frequently by patients in the HFA-MDI group (0.7% before randomization versus 3.4% after randomization). This, however, was an expected finding as the HPA134a formulation does have a different taste to the CFC formulation. No difference between formulations was observed in the incidences of coughing or paradoxical bronchospasm, The incidence of falls in FEV1 >15% within 15 min following inhalation at each of the clinic visits was 1.2% for both CFC- and HFA-MDIs. In conclusion, administration of a fenoterol/ipratropium bromide combination via hydrofluoroalkane-metered dose inhaler is as safe as delivery by the currently available chlorofluorocarbon-metered dose inhaler, in an extended population of patients with CAO under normal prescribing conditions.
  • Author:
    Denyer J; Pavia D; Zierenberg B
    Title:
    New liquid drug aerosol devices for inhalation therapy.
    Source:
    Eur Respir Rev 10, 187-191 (2000)
    Abstract:
    The scope of the planned European Respiratory Society (ERS) nebulizer guidelines must define clearly what devices are included. This paper will discuss four new liquid aerosol devices for inhalation therapy and how they compare with existing nebulizers. The Respimat and Aer(x) devices are combined drug formulation and delivery system. The Respimat is a propellant-free, multidose inhaler, not requiring a battery power source and which can be reused by replacing the drug cartridge. The Aer(x) system has a drug vial with an integral array of holes, it is breath activated and obviates the requirement for patients to remember and comply with instructions for use. The Halolite and AeroNeb are stand-alone delivery devices where the drug is supplied separately from the device. The HaloLite uses adaptive aerosol delivery and a precise preset dose is delivered to each patient. The AeroNeb is a silent and compact nebulizer using novel atomization technology which eliminates the compressor required with a pneumatic nebulizer. In the clinic a nebulizer is considered as a device used to generate an aerosol from an aqueous drug solution or suspension, which is supplied separately. A definition which follows the current understanding of the clinician could increase the rate of adoption of the guidelines and their effective application.
  • Author:
    Newman S; Pitcaim G; Steed K; Harrison A; Nagel J
    Title:
    Deposition of fenoterol from pressurized metered dose inhalers containing hydrofluoroalkanes.
    Source:
    J Allergy Clin Immunol 104 (6), S253-S257 (1999)
    Abstract:
    The objective of this study were 1) to compare the deposition patterns in the human respiratory tract of Berodual (fenoterol + ipratropium bromide) pressurized metered dose inhalers (pMDIs) formulated with chlorofluorocarbons and hydrofluoroalkane-134a and hydrofluoroalkane-227, in 10 volunteers and 2) to assess the effect of actuator nozzle diameter on the deposition pattern of a solution formulation of Berodual containing hydrofluoroalkane-134a. The data suggest that the total and regional lung deposition of hydrofluoroalkane-based pressurized aerosol formulations is highly product-specific and that changes in bioavailability can be brought about by varying both the constituents of the formulation and the design of the actuator. DERWENT-Abstract. 10 Healthy volunteers (5 male) received 2 metered doses on each study day (total, 100 ug fenoterol and 40 ug ipratropium bromide). When comparing chlorofluorcarbon, hydrofluoroalkane-134a and hydroalkane-227 formulations, mean lung depositions averaged 8.0 ug, 13.4 ug and 8.8 ug fenoterol, respectively, for the 3 formulations, with the difference between chlorofluorocarbon and hydrofluoroalkane-134a being significant. In a study in 9 volunteers, lung deposition showed a significant inverse correlation with actuator nozzle diameter for the hydrofluoroalkane-134a formulation, averaging 12.8, 15.2 and 18.0 ug fenoterol for 0.3 mm, 0.25 mm and 0.2 m, respectively. BY comparison, lung deposition averaged 15.5 ug for the chlorofluorcarbon formulation.There were no significant differences in the regional deposition patterns within the lungs for the 4 study legs.
  • Author:
    Hochrainer D; Zierenberg B
    Title:
    Evaporation and deposition of ethanol droplets from the Respimat.
    Source:
    12th Biennial Cong of the Int Soc for Aerosols in Medicine, Vienna (Austria), Jun 12-16, 1999J Aerosol Med 12 (2), 142 Abstr 201 (1999)
  • Author:
    Newman SP; Steed KP; Sohal AK; Reader SJ
    Title:
    Low ocular and facial deposition in vitro from Respimat, a novel soft mist inhaler.
    Source:
    J Aerosol Med 12, 116 Abstr 102 (1999)
  • Author:
    Vermeulen J; Boshof L; Lowe LS
    Title:
    Fenoterol delivered via HFA metered dose inhaler (MDI) is as safe and effective as CFC delivery in the long-term treatment of children with asthma.
    Source:
    1999 Ann Cong of the European Respiratory Soc, Madrid (Spain), Oct 9-13, 1999Eur Respir J 14 (Suppl 30), 180S Abstr P1267 (1999)
  • Author:
    Pavia D; Dewberry H
    Title:
    Low incidence of paradoxical bronchoconstriction for bronchodilator drugs administered from either Respimat or CFC-MDIs.
    Source:
    1999 Int Conf of the American Thoracic Soc, San Diego (USA), Apr 23-28, 1999Am J Respir Crit Care Med 159 (3 pt 2), A116 Abstr (1999)
  • Author:
    Sharma D; Reader S; Spiteri M; Brown A; Patel KR
    Title:
    The safety of inhaled ethanolic and aqueous solutions administered from Respimat in hyperreactive (PC20 </= 8 mg/ml methacholine) asthmatic patients.
    Source:
    Int Conf of the American Thoracic Soc, San Diego (USA), Apr 23-28, 1999Am J Respir Crit Care Med 159 (3 pt 2), A116 Abstr (1999)
  • Author:
    Clauzel AM; Abouda K; Iacono P; Jirou-Najou JL; Rominger KL; Peil H
    Title:
    Plasma concentrations of fenoterol as powder form compared to metered dose inhaler: relationship with side effects.
    Source:
    1998 Int Conf of the American Thoracic Soc, Chicago (USA), Apr 24-29, 1998Am J Respir Crit Care Med 157 (3) (Suppl), A400 Abstr (1998)
  • Author:
    Reisner C; Ferguson GT; Menjoge S; Andel AE van; Dorinsky P; Serby CW; Witek TJ
    Title:
    Superiority of Combivent metered dose inhaler containing albuterol and ipratropium over Proventil containing albuterol alone for reversibility testing in chronic obstructive pulmonary disease (COPD).
    Source:
    1998 Clinical World Cong on Diseases of the Chest, Toronto (Canada), Nov 8-12, 1998Chest 114 (4) (Suppl), 373S-374S Abstr (1998)
  • Author:
    Iacono P; Guemas E; Leclerc V; Thebault JJ
    Title:
    Cumulative dose response study comparing a new soft mist inhaler with a conventional metered dose inhaler (MDI) for delivery of ipratropium bromide in patients with COPD.
    Source:
    1998 Int Conf of the American Thoracic Soc, Chicago (USA), Apr 24-29, 1998Am J Respir Crit Care Med 157 (3 pt 2), A800 Abstr (1998)
  • Author:
    Goldberg J; Freund E; Jahnel B; Hinzmann R
    Title:
    Combination fenoterol/ipratropium bromide delivered via a new soft mist inhaler: dose-range finding study in patients with asthma, in comparison with a conventional metered dose inhaler (MDI).
    Source:
    1998 Int Conf of the American Thoracic Soc, Chicago (USA), Apr 24-29, 1998Am J Respir Crit Care Med 157 (3 pt 2), A401 Abstr (1998)
  • Author:
    Newman SP; Brown J; Steed KP; Reader SJ; Kladders H
    Title:
    Lung deposition of fenoterol and flunisolide delivered using a novel device for inhaled medicines: comparison of Respimat with conventional metered-dose inhalers with and without spacer devices.
    Source:
    Chest 113 (4), 957-963 (1998)
    Abstract:
    STUDY OBJECTIVES: To compare lung deposition of fenoterol or flunisolide administered from a novel, multidose inhalation device delivering liquid droplets (RESPIMAT; Boehringer Ingelheim Ltd; Bracknell, UK) or from conventional metered-dose inhalers (MDIs) with and without spacers. DESIGN: Two randomized, three-way crossover studies. SETTING: Clinical research laboratory. PARTICIPANTS: Healthy, nonsmoking volunteers. INTERVENTIONS: In one study, radiolabeled aerosols of fenoterol from the RESPIMAT device and from a conventional MDI with or without an Aerochamber spacer (Trudell Medical; London, Ontario Canada). In the second study, radiolabeled aerosols of flunisolide from a RESPIMAT device, from a RESPIMAT device modified by inclusion of a baffle/impactor in the mouthpiece, and from a conventional MDI with an Inhacort spacer (Boehringer Ingelheim; Ingelheim, Germany). MEASUREMENTS AND RESULTS: Assessment of the deposition of fenoterol or flunisolide in the lung and oropharynx using gamma scintigraphy. Safety was assessed based on reported adverse effects and spirometry (FEV1, FVC, and peak expiratory flow rate) to detect any paradoxical bronchoconstriction. The RESPIMAT device delivered significantly more fenoterol to the lungs than either an MDI alone or an MDI with Aerochamber (39.2% vs 11.0% and 9.9% of metered dose, respectively; p<0.01). Oropharyngeal deposition of fenoterol from the new device was lower than that from the MDI (37.1% vs 71.7%, respectively; p<0.01). The RESPIMAT device deposited significantly more flunisolide in the lungs compared with MDI plus spacer (44.6% vs 26.4%, respectively; p<0.01), while resulting in similar oropharyngeal deposition (26.2% vs 31.2%, respectively). Introduction of a baffle into the RESPIMAT system reduced lung deposition of flunisolide to 29.5%, and oropharyngeal deposition to 7.8% (p<0.01). CONCLUSION: The RESPIMAT device may prove to be an effective alternative to MDIs for the administration of inhaled bronchodilators and corticosteroids. The high lung deposition and low oropharyngeal deposition may lead to improved efficacy and tolerability of inhaled medications, especially corticosteroids.
  • Author:
    Schweisfurth H; Wettengel R; Doehring E; Stechert R; Zimmermann T
    Title:
    Therapeutic comparison of the inhalation of 0.2 mg fenoterol as one application from a piezoelectric inhaler and as one puff from a metered dose inhaler.
    Source:
    1997 Int Conf of the American Thoracic Soc, San Francisco (USA), May 16-21, 1997Am J Respir Crit Care Med 155 (4 pt 2), A281 Abstr (1997)
  • Author:
    Freund BWJ; Zierenberg B; Eicher J; Dunne S
    Title:
    The Respimat system (BINEB); a new approach to inhalation therapy.
    Source:
    J Aerosol Med 10, 246 Abstr SV-5 (1997)
  • Author:
    Newman SP; Brown J; Steed KP; Reader SJ; Kladders H
    Title:
    Lung deposition of fenoterol from Respimat, a novel inhaler device for pulmonary drug delivery.
    Source:
    J Aerosol Med 10, 268 Abstr PD5-12 (1997)
  • Author:
    Vincken W; Aumann J; Radermecker M; Slabbynck H; Stappaerts I; Demedts M; Moonen D
    Title:
    Comparison of pharmacodynamics, efficacy and safety of fenoterol inhaled from a novel pocket-sized inhaler and from a metered-dose inhaler (MID).
    Source:
    Ann Cong of the European Respiratory Soc (ERS), Berlin (Germany), Sep 20-24, 1997Eur Respir J 10 (Suppl 25), 239S Abstr P1535 (1997)
  • Author:
    Resiner C; Ferguson GT; Menjoge S; Serby CW; Witek TJ
    Title:
    Superiority of a combination metered-dose inhaler containing albuterol and ipratropium over albuterol and ipratropium alone for reversibility testing in chronic obstructive pulmonary disease (COPD).
    Source:
    1997 Chest - Moving toward the Future with Patient-Centered Care, New Orleans (USA), Oct 26-30, 1997Chest 112 (3) (Suppl), 82S Abstr (1997)
  • Author:
    Pitcairn GR; Brown J; Steed KP; Reader SJ; Kladders H; Newman SP
    Title:
    High lung deposition of fenoterol from Respimat, a novel soft-mist inhaler.
    Source:
    American Assoc of Pharmaceutical Scientists (AAPS) Ann Mtg, Boston (USA), Nov 2-6, 1997Pharm Res 14 (11) (Suppl), S143 Abstr 1407 (1997)
  • Author:
    Steed KP; Towse LJ; Freund B; Newman SP
    Title:
    Lung and oropharyngeal depositions of fenoterol hydrobromide delivered from the prototype III hand-held multidose Respimat nebuliser.
    Source:
    Eur J Pharm Sci 5, 55-61 (1997)
  • Author:
    Zierenberg B
    Title:
    Optimizing the in vitro performance of respimat.
    Source:
    J Aerosol Med 12 (Suppl 1), S19-S24 (1999)
    Abstract:
    Aerosolization of a drug solution in a handheld device for inhalation therapy can be achieved either by vibration or extrusion through a fine nozzle. The latter method does not necessitate the use of an electrical power source and has been developed further in Respimat. The device was adapted for mass production, selecting appropriate materials for the desired size and weight as well as for stability and technical performance. After optimization of the nozzle design, Respimat produced encouraging results in its first lung deposition study in volunteers compared with a chlorofluorocarbon-driven metered dose inhaler (CFC-MDI). Respimat is a reusable device with a mode of action that differs from those of other inhalers. The mechanical power from a coiled spring forces a metered volume of drug solution through a nozzle in a unique component, the uniblock. The convergence of two fine jets of liquid generates a slow-moving aerosol of soft mist. The fine particle fraction in the aerosol, determined from experiments with the Anderson Cascade Impactor (Anderson Instruments, Inc., Smyrna, GA), is approximately 66% for an aqueous drug solution and 81% for an ethanolic solution. This value is about 2.5 times higher than the fine particle fractions determined for CFC-MDIs, and the velocity is about five times lower (e.g., 10 m/s for an aqueous solution), with both factors contributing to the improved lung deposition. In addition, the dose release duration from Respimat is considerably longer than that from CFC-MDIs at approximately 1.2 seconds, allowing more time for the patient to coordinate actuation and inspiration. The reliability and consistency of dose delivery from Respimat also have been confirmed.
  • Author:
    Maesen JPV; Noord JA van; Smeets JJ; Greefhorst APM; Dewberry H; Cornellisen PJG
    Title:
    Dose-rang finding study comparing a new soft mist inhaler with a conventional metered dose inhaler (MDI) to deliver fenoterol in patients with asthma.
    Source:
    ERS Ann Cong, Berlin (Germany), Sep 20-24, 1997.Eur Respir J 10 (Suppl 25), 128S (1997)
  • Author:
    Hochrainer D; Zierenberg B
    Title:
    Evaporation and deposition of ethanol droplets from the respimat.
    Source:
    12th Int Cong of the Int Soc for Aerosols in Medicine (ISAM), Vienna (Austria), Jun 12-16, 1999
  • Author:
    Maesen FPV; Greefhorst LPM; Smeets JJ; Wald FDM; Cornelissen PJG
    Title:
    Therapeutic equivalence of a novel HFA 134a-containing metered-dose inhaler and the conventional CFC inhaler (Berodual (R)) for the delivery of a fixed combination of fenoterol/ipratropium bromide.
    Source:
    Respiration 64 (4), 273-280 (1997)
    Abstract:
    The efficacy and safety of a novel fenoterol/ipratropium bromide metered-dose inhaler (MDI) formulated with a non-chlorinated propellant, HFA134a, has been compared with placebo and the conventional chlorofluorocarbon (CFC)-containing fenoterol/ipratropium bromide inhaler (Berodual(TM)) in asthmatic patients. Fifty-two patients were enrolled in two centres. The fenoterol/ipratropium bromide treatment produced significantly (p < 0.0001) greater bronchodilatation than placebo. There were no significant differences between the mean peak and average forced expiratory volume in the first second (FEV1) for patients receiving 2 puffs of the fenoterol/ipratropium bromide HFA134a inhaler and the conventional CFC inhaler. In addition, time to onset and duration of efficacy were comparable for these two treatments. None of the patients showed a fall of <= 15% in baseline FEV1 or needed rescue medication within 30 min after inhalation of the test drug. No paradoxical bronchoconstriction was observed as measured by sGaw. The two inhaler formulations were well tolerated. A taste-related complaint, lasting for a few minutes after inhalation, was reported by a higher proportion of patients who inhaled the HFA134a formulation, mainly by patients selected in one of the two centres. In conclusion, a dose of 100 mug fenoterol/40 mug ipratropium bromide inhaled from a MDI containing HFA134a propellant is safe and provides effective bronchodilatation of equivalent degree, onset and duration of action to the same dose from the conventional CFC formulation.
  • Author:
    Zierenberg B
    Title:
    Metered dose nebulisation. The respimat (R)(BINEB) a new approach to inhalation therapy.
    Source:
    Forum Seminar: "New Horizons in Pulmonary Drug Delivery", London (Great Britain), Oct 1-2, 1996
  • Author:
    Schmelzer C; Froemder A
    Title:
    The most important parameters for development of pressurized metered dose inhalers with non-CFC propellants.
    Source:
    42nd Ann Cong of the APV, Mainz (Germany), Mar 6-9, 1996Eur J Pharm Biopharm 42 (Suppl), 8S Abstr 114 (1996)
  • Author:
    Schmelzer C; Froemder A; Nagel J
    Title:
    Comparison of properties of solution type- and suspension type formulations of pressurized metered dose inhalers with non-CFC propellants.
    Source:
    42nd Ann Cong of the APV, Mainz (Germany), Mar 6-9, 1996Eur J Pharm Biopharm 42 (Suppl), 8S Abstr 115 (1996)
  • Author:
    Zierenberg B; Eicher J; Dunne S; Freund B
    Title:
    Boehringer Ingelheim Nebulizer BINEB. A new approach to inhalation therapy.
    Source:
    Respiratory Drug Delivery V, Arizona (USA), Apr 1996, 187-194 (1996)
  • Author:
    Dunne S; Eicher J; Freund B; Hochrainer D; Zierenberg B
    Title:
    BINEB, a novel propellant-free multi-dose Nebulizer with high lung deposition.
    Source:
    42th Ann Cong of the APV, Mainz (Germany), Mar 7-9, 1996J Aerosol Med 9, 548 (1996)
  • Author:
    Rajendran N; Gerhart J; Vana S; Ball DJ; MacGregor TR; Pack FD; Stoll RE; Aranyi C
    Title:
    Subchronic nose-only inhalation toxicity study in rats with atrovent HFC 134a formulation using an aerosol generation system with metered dose inhalers.
    Source:
    Fundam Appl Toxicol 30 (1 pt 2), 20 Abstr 104 (1996)
    Abstract:
    Sprague-Dawley rats were exposed to aerosols of Atrovent HFC 134a Formulation of Ipratropium Bromide (IB) for up to 4 hours/day, 7 days/week for 13 weeks in 52-port, flow-past, nose-only exposure chambers. The aerosols were dispensed with Metered Dose Inhalers using an IITRI-designed aerosol generation system. Twenty rats/sex/group were exposed to 21.9, 41 or 39.2 µg// IB, or 1.1, 4.0 or 7.5 mg/kg/day of IB, respectively. Additionally, three control groups were exposed to Filtered Air, to the HFC 134a propellant (Vehicle Control), and to a Positive Control consisting of 22.5 µg/J IB or 1.1 mg/kg/day of IB in CFC (chlorofluorocarbon) propellant. Urine from five rats/sex/group was analyzed for ipratropium after 1 day, and 7 and 13 weeks of exposure. Comprehensive gross necropsy and histopathological examinations were preformed on 15 rats/sex/group. No overt signs of toxicity were observed during the study. Statistically significant decreases in body weight and food consumption were observed in the Mid and High dose male rats. Non-concentration-dependent mild hemoconcentration and increased serum albumin levels were observed in IB-exposed animals. At all time points and dose levels, inpratropium was absorbed into the systemic circulation of rats, but did not accumulate. The absorption was proportional to the dose of Atrovent 134a Formulation administered. No gross lesions were observed at necropsy. Histopathologically, a treatment-related increased incidence of chronic suppurative rhinitis in the nasal turbinates was observed in the Mid and High dose animals. Histopathologic changes associated with CFC administration included increased incidence and/or severity and/or increased anatomic distribution of diffuse intracytoplasmic eosinophilic substance within the epithelial cells of the nasal mucosa in one or more anatomic sites and/or levels. Based on these data, the no effect dose level for the Atrovent HFC 134a Formulation was determined to be 1.1 mg/kg/day. These data also indicated that the maximum tolerated dose exceeded the maximum feasible targeted inhaled dose of 9.2 mg/kg/day, achieved under the experimental conditions employed in this study. Additionally, the in-life toxicity, inhalation exposure bioavailability and histopathology for the Atrovent HFC 134a Formulation was comparable or less significant than that of the animals exposed to the Atrovent CFC Formulation.
  • Author:
    Newman SP; Steed KP; Towse LJ; Zierenberg B
    Title:
    The BINEB (final prototype): a novel hand-held, multidose nebuliser evaluated by gamma scintigraphy.
    Source:
    Ann Cong of the Eur Respiratory Soc (ERS), Stockholm (Sweden), Sep 7-11, 1996Eur Respir J 9 (Suppl 23), 441s P2736 (1996)
  • Author:
    Maesen FPV; Smeets JJ; Smeets P; Wald FDM; Cornelissen PJG
    Title:
    A pilot study to compare the efficacy and safety of ipratropium bromide administered from an MDI with a metered dose solution from a novel device (BINEB).
    Source:
    Eur Respir J 8 (Suppl 18), 258S Abstr P1302 (1995). Eur Respir J 8 (Suppl 19), 426S Abstr P2096 (1995) Ann Cong of the Eur Respiratory Soc (ERS), Barcelona (Spain), Sep 16-20, 1995
  • Author:
    Steed KP; Freund B; Towse L; Newman SP
    Title:
    High lung deposition of fenoterol from BINEB, a novel multiple dose nebuliser device.
    Source:
    Ann Cong of the Eur Respiratory Soc (ERS), Barcelona (Spain), Sep 16-20, 1995Eur Respir J 8 (Suppl 18), 204S Abstr 1061 (1995)
  • Author:
    Steed KP; Zierenberg B; Reader S; Newman SP
    Title:
    Lung deposition of flunisolide from BINEB, a novel multiple dose nebuliser, is twice that from a pressurised metered dose inhaler.
    Source:
    Ann Cong of the Eur Respiratory Soc (ERS), Barcelona (Spain), Sep 16-20, 1995Eur Respir J 8 (Suppl 18), 122S Abstr P0640 (1995)
  • Author:
    Zierenberg B; Hochrainer D
    Title:
    The Respimat - an inhaler with ultrasonic nebulization.
    Source:
    3. Grafschafter Kolloquium "Aerosole und Lunge", Schmallenberg (Germany), Apr 24-25, 1992