Inhalationstherapie mit dem Respimat® Soft Inhaler bei Asthma und COPD

Zusammenfassung

Für die Behandlung obstruktiver Atemwegserkrankungen ist die Entwicklung verbesserter Inhalationssysteme von ebenso großer Bedeutung wie die Einführung neuer inhalierbarer Pharmaka. In den letzten Jahren hat es zahlreiche Neuentwicklungen und technische Modifikationen an bereits vorhandenen Inhalationssystemen gegeben. Jedes dieser Systeme hat ganz spezifische Eigenschaften, so wie es auch grundsätzliche Unterschiede zwischen treibmittelgetriebenen Dosieraerosolen (pMDI), Trockenpulversystemen (DPI), Ultraschall- und Düsenverneblern gibt. Keines der Geräte kann bisher als „ideal” angesehen werden. Unter Berücksichtigung der Erkenntnisse über bisher genutzte Systeme wurde der Respimat® Soft Inhaler (Respimat® SI) entwickelt und in Deutschland Anfang 2004 in den Markt eingeführt. Ziel der Entwicklung war es, die typischen und langjährig bekannten Nachteile der MDI ebenso zu vermeiden wie die der DPI, die Vorteile des Taschenformats aber im Gegensatz zu den typischen Ultraschall- und Düsenverneblern beizubehalten. Der Respimat® SI arbeitet ohne Treibmittel oder elektrische Energie/Batterien. In Lösung befindliche Wirkstoffe werden mit hohem über eine Feder generierten Druck durch zwei konvergent aufeinander gerichtete Mikrodüsen gepresst. Dadurch entsteht über eine relativ lange Zeit (Freisetzungsdauer 1,5 Sek.) eine sich sehr langsam ausbreitende Aerosolwolke mit einem hohen Massenanteil so genannter Feinpartikel. Die oropharyngeale Deposition ist durch diese Charakteristika reduziert, die pulmonale entsprechend hoch. Die Koordinationsanforderungen sind durch einfache Bedienbarkeit und vor allem durch die langlebige Aerosolwolke gering. Die Aerosolcharakteristik ist unabhängig vom Inspirationsfluss der Patienten. Der Respimat® SI kommt den Idealeigenschaften eines Inhalationsgerätes näher als alle bisher verfügbaren Geräte und muss daher als eine bedeutende Neuentwicklung angesehen werden.

Abstract

Developing more effective and convenient inhalation devices for the treatment of obstructive pulmonary diseases is at least as important as designing new drugs. In recent years, existing inhalation systems have undergone many technical modifications and there have also been many new developments. All of these systems have their own particular attributes and characteristics. Two fundamentally different modes of operation are represented by propellant-driven metered-dose inhalers (pMDI) on the one hand and dry powder inhalers (DPI) on the other. However, none of the systems developed so far can be considered ideal. The Respimat® Soft Inhaler (Respimat® SI) was developed in the light of experience with previous systems and was launched in Germany at the beginning of 2004. The aim in developing this new type of inhaler was to avoid the well-known drawbacks typically associated with pMDI and DPI. The Respimat® SI requires neither a chemical propellant nor batteries. The active ingredients are dissolved in water and the solution is atomised using mechanical energy only imparted by a spring which, when released, provides the power to force the solution through an extremely fine nozzle system. Two fine jets of liquid are produced. They converge at an optimised angle and the resulting impact generates a fine mist which is slow-moving and lasts for about 1.5 seconds; moreover, a high proportion of the droplets fall into the fine particle fraction. All of these features allow excellent lung deposition and reduced oropharyngeal deposition. Coordination between actuation and inhalation is less critical as compared with pMDI due to the fact that the mist is both slow-moving and long-lasting. A further advantage is that the mist is generated independently of the patient’s inspiratory flow. The Respimat® SI meets the requirements for an ideal inhaler better than any other previous device and must therefore be regarded as a significant new development.

Literatur

• 1 Ariyananda P L, Agnew J E, Clarke S W. Aerosol delivery systems for bronchial asthma.  Postgrad Med J. 1996;  72 151-156
• 2 Ganderton D. General factors influencing drug delivery to the lung.  Respir Med. 1997;  91 (Suppl A) 13-16
• 3 Ganderton D. Targeted delivery of inhaled drugs: Current challenges and future goals.  J Aerosol Med. 1999;  12 (Suppl 1) 3-8
• 4 Pavia D. Efficacy and safety of inhalation therapy in chronic obstructive pulmonary disease and asthma.  Respirology. 1997;  2 (Suppl 1) 5-10
• 5 Voshaar T H, App E M, Berdel D. et al . Empfehlungen für die Auswahl von Inhalationssystemen zur Medikamentenverabreichung.  Pneumologie. 2001;  55 579-586
• 6 Voshaar T. Inhalative Atemwegstherapie: Technik und Handhabung der Devices - häufigste Fehler.  Med Klein. 2002;  97: Suppl II 2-6
• 7 Köhler D, Fleischer W. Theorie und Praxis der Inhalationstherapie. München: Arcis Verlag 2000
• 8 Byron P R, Patton J S. Drug delivery via the respiratory tract.  J Aerosol Med. 1994;  7 49-75
• 9 Heyder J. Deponierung von Aerosolteilchen im Atemtrakt des Menschen. In: Scheuch G (Ed.) Aerosole in der Inhalationstherapie, Grundlagen und Anwendung. München-Deisenhofen: Dustri Verlag 1997: 1-10
• 10 Köhler D, Fleischer W, Matthys H. Depositionsmuster von Dosieraerosolen im menschlichen Organismus.  Atemw Lungenkrkh. 1985;  11 340-341
• 11 Martonen T B, Katz I. Deposition mechanics of pharmaceutical particles in human airways. In: Hickey AJ (Hrsg.): Inhalation Aerosols: Physical and Biological Basis for Therapy. New York: Marcel Dekker 1996: 3-28
• 12 Martonen T B, Katz I. Deposition patterns of aerosolized drugs within human lungs: effects of ventilatory parameters.  Pharm Res. 1993;  10 871-878
• 13 Smith K J, Chan K H, Brown K F. Influence of flow rate on aerosol particle size distributions from pressurized and breath-actuated inhalers.  J Aerosol Med. 1998;  11 231-245
• 14 Roeder S, Müllinger B, Brand P. et al .Optimierung von Atemmanövern in der Aerosoltherapie durch eine mechanische Atemflusslimitierung. In: Aerosole in der Inhalationstherapie IV. München-Deisenhofen: Dustri 2000
• 15 Brand P. Neue Strategien in der Inhalationsdosimetrie. In: Scheuch G: Aerosole in der Inhalationstherapie II. München-Deisenhofen: Dustri, München 1998
• 16 Dalby R N, Tiano S L, Hickey A J. Medical devices for the delivery of therapeutic aerosols to the lung. In: Hickey AJ (Hrsg.): Inhalation Aerosols: Physical and Biological Basis for Therapy. New York: Marcel Dekker 1996: 441-474
• 17 Hickey A J, Concessio N M, Oort M M van. et al . Factors influencing the dispersion of dry powders as aerosols.  Pharm Tech. 1994;  8 58-82
• 18 June D. Achieving the change: challenges and successes in the formulation of CFC-free MDI's.  Eur Respir Rev. 1997;  7 32-34
• 19 Leach C L. Approaches and challenges to use freon propellant replacements.  Aerosol Sci Technol. 1995;  22 329-334
• 20 Hochrainer D, Hölz H. Comparison of the velocities of clouds delivered from Respimat® Soft Mist^TM Inhaler and metered dose inhalers.  J Aerosol Med. 2001;  14 (3) abstract 379-421
• 21 Newman S A, Morén F, Pavia D. et al . Deposition of pressurized suspension aerosols inhaled through extension devices.  Am Rev Respir Dis. 1981;  124 17-20
• 22 Crompton G. Problems patients have using pressurized aerosol inhalers.  Eur J Respir Dis. 1982;  63 (Suppl. 119) 101-104
• 23 Petro W, Gebert P, Lauber B. Ursachen fehlerhafter Anwendung von Dosieraerosolen.  Pneumologie. 1994;  48 191-196
• 24 Giraud V, Roche N. Misuse of corticosteroid metered-dose inhaler is associated with decreased asthma stability.  Eur Respir J. 2002;  19 246-251
• 25 Brown P H, Blundell G, Greening A P. et al . Do large spacer devices reduce the systemic effects of high dose inhaled corticosteroids?.  Thorax. 1990;  45 736-739
• 26 Newman S P, Millar A B, Lennard-Jones T R. et al . Improvement of pressurized aerosol deposition with the Nebuhaler spacer device.  Thorax. 1984;  39 935-941
• 27 Holzner P, Müller B W. An in vitro evaluation of various spacer devices for metered dose inhalers using the twin impinger.  Int J Pharm. 1994;  106 69-75
• 28 Janssens H M, Devadason S G, Hop W CJ. Variability of aerosol delivery via spacer devices in young children in daily life.  Eur Respir J. 1999;  13 787-791
• 29 Dewsbury N J, Kenyon C J, Newman S P. The effect of handling techniques on electrostatic charge on spacer devices: a correlation with in vivo particle size analysis.  Int J Parm. 1996;  137 216-264
• 30 Chuffart A. Factors effecting the efficiency of aerosol therapy with pMDI through plastic spacers.  Swiss Med Wkly. 2001;  131 14-18
• 31 Hindle M, Byron P R. Dose emissions from marketed dry powder inhalers.  Int J Pharmaceut. 1995;  116 169-177
• 32 Köhler D, Grossmann J, Schümichen C. et al . Comparing efficacy of various adrenergic MDIs with the recommended expander systems.  Bull Europ Physiopath Resp. 1986;  22 662
• 33 Meakin B J, Ganderton D, Panza I. et al . The effect of flow rate on drug delivery from the Pulvinal, a high-resistance dry powder inhaler.  J Aerosol Med. 1998;  11 143-152
• 34 Newman S P, Hollingworth A, Clark A R. Effect of different modes of inhalation on drug delivery from a dry powder inhaler.  Int J Pharm. 1994;  102 127-132
• 35 Visser J. Van der Waals and other cohesive forces affecting powder fluidization.  Powder Technol. 1998;  58 1-10
• 36 Zanen P, Spiegel P I van, Kolk H van der. et al . The effect of the inhalation flow on the performance of a dry powder inhalation system.  Int J Pharm. 1992;  81 199-203
• 37 Everard M L, Devadason S G, Le Souef P N. Flow early in the inspiratory manoeuvre affects the aerosol particle size distribution from a Turbuhaler.  Respir Med. 1997;  91 624-628
• 38 Zainudin B MZ, Biddiscombe M, Tolfree S EJ. Comparison of bronchodilator responses and deposition patterns of salbutamol inhaled from a metered dose inhaler, as a dry powder, and as a nebulised solution.  Thorax. 1990;  45 469-473
• 39 Ad Hoc Committee on Health Literacy for the Council of Scientific Affairs, American Medical Association, Health Literacy . Report of the Council of Scientific Affairs.  JAMA. 1999;  281 552-557
• 40 Armitage J M, Williams S J. Inhaler technique in the elderly.  Age and Ageing. 1988;  17 275-278
• 41 Denyer J, Pavia D, Zierenberg B. New liquid aerosol devices for inhalation therapy.  Eur Respir Rev. 2000;  10 187-191
• 42 Schmelzer C, Bagel S. Microbiological integrity of Respimat® Soft Mist^TM Inhaler (SMI) cartridges after use in COPD patients.  J Aerosol Med. 2001;  14 (3) 385 (P1-3)-385(P1-3)
• 43 Zierenberg B, Eicher J, Dunne S. et al .Boehringer Ingelheim nebulizer BINEB® a new approach to inhalation therapy. In: Dalby R (ed.): Respir Drug Deliv V. Buffalo Grove IL: Interpharm Press 1996: 187-193
• 44 Zierenberg B. Optimizing the in vitro performance of Respimat®.  J Aerosol Med. 1999;  12 (Suppl 1) 19-24
• 45 Spallek M, Hochrainer D, Wachtel H. Optimizing nozzles for soft mist inhalers.  Respiratory Drug Delivery VIII. 2002;  2 375-378
• 46 Wachtel H, Ziegler J. Improved assessment of inhaler device performance using laser diffraction.  Respiratory Drug Delivery VIII. 2002;  2 379-382
• 47 Noord J A van, Smeets J J, Creemers J PHM. Delivery of fenoterol via Respimat®, a novel soft mist inhaler.  Respiration. 2000;  67 672-678
• 48 Zierenberg B, Eicher J. The Respimat®, a new soft mist inhaler for delivering drugs to the lung. In: Rathbone MJ, Hadgraft J, Roberts MS (ed.): Modified-release drug delivery technology. New York: Marcel Dekker Inc 2002: 925-933
• 49 Newman S P, Brown J, Steed K P. Lung deposition of fenoterol and flunisolide delivered using a novel device for inhaled medicines. - Comparison of Respimat® Soft Mist^TM Inhaler with conventional pMDIs with and without spacer devices.  Chest. 1998;  113 957-963
• 50 Wilding I R, Pitcairn G R, Reader S. et al . Respimat® Soft Mist^TM Inhaler delivers inhaled corticosteroid to the lungs more efficiently than a Turbuhaler dry powder inhaler or a pressurized metered dose inhaler.  AAPS Pharm Sci. 2002;  4 (4) abstract W 4130
• 51 Newman S P, Steed K P, Reader S J. Efficient delivery to the lungs of flunisolide aerosol from a new portable hand-held multidose nebulizer.  J Pharm Sci. 1996;  85 960-964
• 52 Steed K P, Towse L J, Freund B. et al . Lung and oropharyngeal depositions of fenoterol hydrobromide delivered from the prototype III hand-held multidose Respimat nebuliser.  Eur J Pharm Sci. 1997;  5 55-61
• 53 Goldberg J, Freund E, Beckers B. et al . Improved delivery of fenoterol plus ipratropium bromide using Respimat® compared with a conventional metered dose inhaler.  Eur Respir J. 2001;  17 225-232
• 54 Kunkel G. Cumulative dose response study comparing a new soft mist inhaler with a conventional MDI for delivery of a fenoterol/ipratropium bromide combination in patients with asthma.  Eur Respir J. 1997;  10 (Suppl. 25) 104
• 55 Kunkel G, Magnussen H, Bergmann K C. et al . Respimat® (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.  Respiration. 2000;  67 306-314
• 56 Vincken W, Bantje T, Middle M V. et al . Long-term efficacy and safety of ipratropium bromide plus fenoterol via Respimat® Soft Mist^TM Inhaler (SMI) versus a pressurised metered-dose inhaler (MDI) in asthma.  Clinical Drug Investigation. 2004;  24 (1) 17-28
• 57 Berg A von, Jeena P M, Soemantri P A. et al . Efficacy and safety of ipratropium bromide plus fenoterol inhaled via Respimat® Soft Mist^TM Inhaler vs. a conventional metered dose inhaler plus spacer in children with asthma.  Pediatric Pulmonology. 2004;  37 (3) 264-272
• 58 Kilfeather S A, Ponitz H H, Beck E. et al . Improved delivery of ipratropium bromide/fenoterol from Respimat® Soft Mist^TM Inhaler in patients with COPD.  Respiratory Medicine. 2004;  98 (5) 387-397
• 59 Schürmann W, Schmidtmann S, Moroni P. et al . Patients prefer Respimat® Soft Mist^TM Inhaler to HFA-MDI.  Prim Care Respir J. 2004;  13 118
• 60 Sharma D. The safety of inhaled ethanolic and aqueous solutions administered from Respimat® in hyperreactive asthmatic patients.  Am J Respir Crit Care Med. 1999;  159 (3 part 2) A116
• 61 Goldberg J. Combination fenoterol/ipratropium bromide delivered via a new soft mist inhaler: dose-range finding study in patients with asthma, in comparison with a conventional MDI.  Am J Respir Crit Care Med. 1998;  157 (Suppl.) A401
• 62 Iacono P. Cumulative dose response study comparing a new soft mist inhaler with a conventional pMDI for delivery of ipratropium bromide in patients with COPD.  Am J Respir Crit Care Med. 1998;  157 (Suppl.) A800
• 63 Pavia D, Dewberry H. Low incidence of paradoxical bronchoconstriction for bronchodilator drugs administered from either Respimat® or CFC-pMDIs.  Am J Respir Crit Care Med. 1999;  157 (Suppl.) A119
• 64 Vincken W. Comparison of pharmacodynamics, efficacy and safety of fenoterol inhaled from a novel pocket-sized inhaler and from MDI.  Eur Respir J. 1997;  10 (Suppl. 25) 239
• 65 Pavia D, Moonen D. Preliminary data from phase II studies with the Respimat®, a propellant-free soft mist inhaler.  J Aerosol Med. 1999;  12 (Suppl. 1) 33-39
• 66 Zhang Y G, Wright W J, Tam W K. et al . Effect of inhaled preservatives on asthmatic subjects. II. Benzalkonium chloride.  Am Rev Respir Dis. 1990;  141 1405-1408
• 67 Miszkiel K A, Beasley R, Rafferty P. et al . The contribution of histamine release to bronchoconstriction provoked by inhaled benzalkonium chloride in asthma.  Br J Clin Pharmac. 1988;  25 157-163