The Science Journal of the American Association for Respiratory Care

Original Contributions

February 2002 / Volume 47 / Number 2 / Page 159

Dry Powder Ipratropium Bromide Is As Safe and Effective As Metered-Dose Inhaler Formulation: A Cumulative Dose-Response Study in Chronic Obstructive Pulmonary Disease Patients

Antoine Cuvelier MD, Jean-François Muir MD, Daniel Benhamou MD, Jean-Claude Guérin MD, Emmanuel Weitzenblum MD, Pierre Zuck MD, Robert Delacenserie MD, André Taytard MD, François Philip-Joet MD, and Philippe Iacono MD

A multi-center, open, randomized, 2-way crossover study was conducted with chronic obstructive pulmonary disease (COPD) patients to compare the safety and efficacy of cumulative doses of ipratropium bromide administered from a pressurized metered-dose inhaler (MDI) or from a breath-activated dry powder inhaler (DPI). Enrolled in the study were 39 patients with moderate to severe COPD and who showed a > or = 15% increase in baseline forced expiratory volume in the first second (FEV1) after 80 micrograms of ipratropium bromide. Thirty-six patients were evaluable for efficacy analysis, and 38 patients were included in the safety analysis group. A significant improvement in pulmonary function was observed following inhalation of cumulative doses of ipratropium bromide (from 20 to 320 micrograms), but no statistically significant difference was found between the 2 formulations. The dose-response curves were similar. There was no statistical difference in area-under-the-curve during the 180 min period after the last dose for any of the pulmonary function variables. Overall, effects on pulse rate, blood pressure, and QT interval on electrocardiogram were no different between the devices. Six mild adverse events occurred in 4 patients: ventricular ectopic beats on electrocardiogram at 270 min with MDI, bad taste with both MDI and DPI, slight transient increase in blood pressure in the same patient during each study day with both MDI and DPI. Two moderate adverse events occurred in 2 patients: transient ventricular ectopic beats on electrocardiograms with DPI at 270 min, moderate bronchospasm with MDI at 200 min. Patients expressed a preference for DPI, which was found to have a better acceptability and appeared to be easier to use than MDI. The new lactose powder formulation of ipratropium bromide inhaled via the breath-activated DPI is a safe and effective alternative to the chlorofluorocarbon-propelled MDI.
Key words: chronic obstructive pulmonary disease, COPD, ipratropium bromide, metered-dose inhaler, MDI, dry-powder inhaler, DPI.
[Respir Care 2002;47(2):159–166]

Introduction

Ipratropium bromide is a quaternary ammonium anticholinergic compound chemically related to atropine. Ipratropium bromide induces bronchodilation through a selective parasympathetic blockade of the bronchial muscarinic receptors. Since cholinergic tone substantially contributes to airway narrowing in patients with chronic obstructive pulmonary disease (COPD), ipratropium bromide is a mainstay in the management of those patients. The bronchodilator action of ipratropium bromide is dose-dependent, and the recommended dose is not a definite dose but rather a range of doses, depending on the subject, the disease, and the severity of the disease. Regular use of ipratropium bromide has been associated with improvement above baseline lung function and in acute response to bronchodilator therapy after 90 days. Long-term treatment with ipratropium bromide could be associated with improvement in dyspnea, especially in a subgroup of responder patients who show > or =15% increase in baseline forced expiratory volume in the first second (FEV1) after administration of 80 micrograms of ipratropium bromide.

Metered-dose inhalers (MDIs) have proven safe, effective, and convenient for delivering ipratropium bromide to COPD patients. However, several drawbacks encountered with MDIs have led to the development and testing of alternative devices such as dry powder inhalers (DPIs). DPIs do not require the coordination of actuation and inhalation that many patients are unable to perform with MDI. Moreover, DPIs use no propellants, such as chlorofluorocarbon (CFC), which contributes to depletion of the ozone layer in the stratosphere. The Montreal Protocol, which was adopted by several governments in 1987 and has been modified 5 times to date, aims to reduce and eventually eliminate emission of man-made ozone-depleting substances. In this context, DPI may be a suitable alternative for administering inhaled drugs. Recently a DPI that uses lactose as an excipient was designed for ipratropium bromide inhalation. Earlier powder inhalation formulations of ipratropium bromide used anhydrous glucose as the carrier substance, but the rate and extent of water uptake is less with lactose than with glucose, so the lactose-excipient DPI is less sensitive to environmental humidity than glucose-excipient DPI.

It is therefore important to study the efficacy of the lactose-excipient DPI and to compare its efficacy and safety profile to other established devices. The aim of the present study was to compare the safety and efficacy of ipratropium bromide in COPD patients when taken as an inhaled powder via the lactose-excipient DPI and as a pressurized aerosol via MDI. We used a cumulative dose-response model and also evaluated the tolerability and patient acceptance of the DPI.

The entire text of this article is available in the printed version of the February 2002 RESPIRATORY CARE.

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