Safety and Efficacy of Proprietary Glycopyrronium MDI in COPD
Bronchodilator medications are central to the symptomatic management of chronic obstructive pulmonary disease (COPD). Inhaled short- and long-acting muscarinic antagonists (SAMAs and LAMAs), such as ipratropium and tiotropium bromide, respectively, are among the main classes of bronchodilators used for the treatment of COPD and have been shown to improve lung function and reduce COPD symptoms. Metered-dose inhalers (MDIs) are the most commonly used devices to deliver treatment to patients with COPD and asthma, comprising approximately 70% of bronchodilator prescriptions. Although they are easy to use and are well-accepted, efforts to comply with federal laws mandating the phasing-out of chlorofluorocarbon propellants have encountered technical barriers in the creation of a stable formulation, which have led several companies to instead pursue the commercialization of dry-powder inhalers (DPIs).
Hollow, porous-particles added to HFA MDIs provide a mechanism for stabilizing suspensions of inhaled drugs, leading to improved physical stability, ability to formulate very low doses, consistent dose-to-dose performance, and high fine-particle fraction (FPF). The large area of the hollow, porous particles allows therapeutic agents to be adsorbed and delivered into the lungs during inhalation. The particles themselves are comprised of distearoyl-phosphatidylcholine (DSPC), a naturally occurring lung surfactant that is used frequently in approved pharmaceutical preparations, and CaCl2. The initial exploration of these respirable porous particles as a delivery platform for inhaled bronchodilator therapy was performed with formoterol as a monotherapy. Another advantage offered by the porous-particle technology includes relatively uniform aerodynamic particle size distribution allowing delivery of drug to the lower respiratory tract with minimized oropharyngeal exposure.
Glycopyrronium (GP) is an antimuscarinic drug that has been approved by the U.S. Food and Drug Administration for systemic administration in multiple clinical scenarios, including as a preoperative agent to reduce the volume of saliva and acidity of gastric secretions. It is a quaternary ammonium derivative that when inhaled results in minimal mucosal absorption and systemic side effects. A dry-powder inhalation formulation of glycopyrronium recently approved in Europe and Japan has demonstrated significant and sustained bronchodilator efficacy over a 24-hour period as well as a positive safety and tolerability profile.
The present study represents the first clinical study of a glycopyrronium metered-dose inhaler (GP MDI) developed using a proprietary lipid-based porous-particle. This study was designed to evaluate the efficacy and safety of 4 doses of GP MDI to serve as the basis for selecting the dose(s) that produce a consistent 12- and/or 24-hour duration of action for more definitive studies. Tiotropium bromide 18 μg [(Spiriva® delivered via the Handihaler®; Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut)(TIO)] was included as an open-label active comparator.
Background
Bronchodilator medications are central to the symptomatic management of chronic obstructive pulmonary disease (COPD). Inhaled short- and long-acting muscarinic antagonists (SAMAs and LAMAs), such as ipratropium and tiotropium bromide, respectively, are among the main classes of bronchodilators used for the treatment of COPD and have been shown to improve lung function and reduce COPD symptoms. Metered-dose inhalers (MDIs) are the most commonly used devices to deliver treatment to patients with COPD and asthma, comprising approximately 70% of bronchodilator prescriptions. Although they are easy to use and are well-accepted, efforts to comply with federal laws mandating the phasing-out of chlorofluorocarbon propellants have encountered technical barriers in the creation of a stable formulation, which have led several companies to instead pursue the commercialization of dry-powder inhalers (DPIs).
Hollow, porous-particles added to HFA MDIs provide a mechanism for stabilizing suspensions of inhaled drugs, leading to improved physical stability, ability to formulate very low doses, consistent dose-to-dose performance, and high fine-particle fraction (FPF). The large area of the hollow, porous particles allows therapeutic agents to be adsorbed and delivered into the lungs during inhalation. The particles themselves are comprised of distearoyl-phosphatidylcholine (DSPC), a naturally occurring lung surfactant that is used frequently in approved pharmaceutical preparations, and CaCl2. The initial exploration of these respirable porous particles as a delivery platform for inhaled bronchodilator therapy was performed with formoterol as a monotherapy. Another advantage offered by the porous-particle technology includes relatively uniform aerodynamic particle size distribution allowing delivery of drug to the lower respiratory tract with minimized oropharyngeal exposure.
Glycopyrronium (GP) is an antimuscarinic drug that has been approved by the U.S. Food and Drug Administration for systemic administration in multiple clinical scenarios, including as a preoperative agent to reduce the volume of saliva and acidity of gastric secretions. It is a quaternary ammonium derivative that when inhaled results in minimal mucosal absorption and systemic side effects. A dry-powder inhalation formulation of glycopyrronium recently approved in Europe and Japan has demonstrated significant and sustained bronchodilator efficacy over a 24-hour period as well as a positive safety and tolerability profile.
The present study represents the first clinical study of a glycopyrronium metered-dose inhaler (GP MDI) developed using a proprietary lipid-based porous-particle. This study was designed to evaluate the efficacy and safety of 4 doses of GP MDI to serve as the basis for selecting the dose(s) that produce a consistent 12- and/or 24-hour duration of action for more definitive studies. Tiotropium bromide 18 μg [(Spiriva® delivered via the Handihaler®; Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut)(TIO)] was included as an open-label active comparator.
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