Beta-hairpin peptidomimetic with elastase inhibitory activity and aerosol dosage forms thereof
Inventors
Ludin, Christian • Keller, Manfred
Assignees
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Publication Number
US-11235023-B2
Publication Date
2022-02-01
Expiration Date
Abstract
The present invention relates to pharmaceutical aerosols comprising a β-hairpin peptidomimetic of formula cyclo(-OctG-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Tyr-DPro-Pro-), or a pharmaceutically acceptable salt thereof, having inhibitory activity against human neutrophil elastase. It further relates to solid or liquid pharmaceutical compositions and kits for preparing and administering such aerosols. The invention can be used for the prevention, management or treatment of pulmonary diseases, such as alpha-1 antitrypsin deficiency (AATD), cystic fibrosis (CF), non-cystic fibrosis bronchiactasis (NCFB), or chronic obstructive pulmonary disease (COPD), or infections, or diseases, or conditions of the lungs, being mediated by or resulting from human neutrophil elastase activity. Thus, the invention further relates to a pharmaceutical composition or a pharmaceutical aerosol comprising the active compound cyclo(-OctG-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Tyr-DPro-Pro-), or any pharmaceutically acceptable salt thereof, for use in a method for the prevention, management or treatment of diseases or conditions of the lungs being mediated by or resulting from human neutrophil elastase activity in a subject.
Core Innovation
The invention provides a pharmaceutical aerosol for pulmonary administration comprising a dispersed liquid phase and a continuous gas phase. The dispersed liquid phase comprises aqueous droplets comprising the active compound cyclo(-OctG-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Tyr-DPro-Pro-) or a pharmaceutically acceptable salt thereof, where OctG is (S)-2-aminodecanoic acid and DPro is D-proline. The aerosol is prepared from a liquid pharmaceutical composition containing the active compound or its pharmaceutically acceptable salt.
The aerosol is defined by droplet size constraints including a mass median diameter from about 1.5 µm to about 5 µm and a droplet size distribution having a geometrical standard deviation from about 1.2 to about 1.7. The liquid pharmaceutical composition includes the active compound in a concentration from about 4 mg/mL to about 100 mg/mL, with dynamic viscosity from about 0.8 mPas to about 1.7 mPas and surface tension from about 25 mN/m to 80 mN/m.
The disclosed kit and delivery concepts include a nebulizer for delivering the pharmaceutical aerosol having the dispersed aqueous droplets and continuous gas phase meeting the specified droplet size and liquid property parameters. The kit can include a liquid pharmaceutical composition directly or a solid pharmaceutical composition dissolvable or dispersible in an aqueous liquid solvent to form the specified liquid composition.
Claims Coverage
The partial content includes three independent claims: a pharmaceutical aerosol, a kit, and a method of preparing and delivering. Across these claims, the inventive coverage centers on five feature groups: the specific active compound identity, the two-phase aerosol structure, the aerosol droplet size distribution parameters, the liquid formulation property ranges, and the nebulizer-driven delivery constraints.
A two-phase pharmaceutical aerosol with defined active compound
The aerosol comprises a dispersed liquid phase and a continuous gas phase, wherein the dispersed liquid phase comprises aqueous droplets comprising cyclo(-OctG-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Tyr-DPro-Pro-) or a pharmaceutically acceptable salt thereof; OctG is (S)-2-aminodecanoic acid and DPro is D-proline.
Droplet size distribution constraints for the dispersed aqueous droplets
The aerosol has a mass median diameter from about 1.5 µm to about 5 µm and a droplet size distribution having a geometrical standard deviation from about 1.2 to about 1.7.
Liquid pharmaceutical composition ranges for active compound and physical properties
The aerosol is prepared from a liquid pharmaceutical composition comprising the active compound or a pharmaceutically acceptable salt thereof, in a concentration from about 4 mg/mL to about 100 mg/mL, having a dynamic viscosity from about 0.8 mPas to about 1.7 mPas and a surface tension from about 25 mN/m to 80 mN/m.
A kit including a nebulizer and a formulation meeting aerosol and fluid parameter constraints
The kit comprises a nebulizer and a liquid composition comprising the active compound or a pharmaceutically acceptable salt thereof, with a concentration from about 4 mg/mL to about 100 mg/mL, dynamic viscosity from about 0.8 mPas to about 1.7 mPas, and surface tension from about 25 mN/m to 80 mN/m, wherein the dispersed liquid phase has a mass median diameter from about 1.5 µm to about 5 µm and a geometrical standard deviation from about 1.2 to about 1.7.
A solid-to-liquid kit option with dissolvable or dispersible solid composition
The kit comprises a nebulizer and a solid pharmaceutical composition for preparing the liquid composition, wherein the solid composition comprises the active compound or a pharmaceutically acceptable salt thereof, and the solid composition is dissolvable or dispersible in an aqueous liquid solvent.
A method using a nebulizer delivering aerosol with minimum delivery rate and specified droplet parameters
The method provides a nebulizer capable of aerosolizing the liquid pharmaceutical composition at a mean delivery rate of at least about 0.8 mg of the active compound per minute, wherein the nebulizer is adapted to emit an aerosol comprising a dispersed liquid phase having a mass median diameter from about 1.5 µm to about 5 µm and a geometrical standard deviation from about 1.2 to about 1.7.
Across the independent claims, coverage centers on pulmonary administration via a nebulizer-delivered aerosol containing cyclo(-OctG-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Tyr-DPro-Pro-) or a pharmaceutically acceptable salt thereof, with defined droplet size distribution and formulation properties, with kit and method variants including a liquid composition option or a solid composition dissolvable or dispersible in an aqueous liquid solvent.
Stated Advantages
Inhibits human neutrophil elastase.
Supported by in vivo neutrophil elastase activity data in models including LPS/fMLP rat and CF sputum, with NE inhibition following single ascending inhaled doses.
Includes GLP-compliant 28-day inhalation toxicity support with NOAELs in rats and monkeys, and first-in-man healthy subject safety support.
Documented Applications
Pulmonary indications associated with neutrophil elastase activity, including alpha-1 antitrypsin deficiency (AATD), cystic fibrosis (CF), non-cystic fibrosis bronchiactasis (NCFB), COPD, and elastase-mediated infections.
Measurement and evaluation of neutrophil elastase activity in vivo, including LPS/fMLP rat model and CF sputum.
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