Beta-hairpin peptidomimetic with elastase inhibitory activity and aerosol dosage forms thereof
Inventors
Ludin, Christian • Keller, Manfred • BRUIJNZEEL, Piet • Zimmermann, Johann • BARTH, Philip • Chevalier, Eric
Assignees
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Publication Number
US-11844823-B2
Publication Date
2023-12-19
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 relates to pharmaceutical aerosol pulmonary administration that inhibits human neutrophil elastase activity. The aerosol comprises a dispersed liquid phase of aqueous droplets containing cyclo(-OctG-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Tyr-DPro-Pro-) and/or a pharmaceutically acceptable salt thereof, together with a continuous gas phase.
The aerosol is characterized by a mass median diameter from about 1.5 m to about 5 m and a geometrical standard deviation from about 1.2 to about 1.7. In one embodiment, the pharmaceutical composition further comprises sodium chloride and optionally one or more pharmaceutically acceptable diluents, excipients or carriers.
The invention also provides methods of treating diseases or conditions of the lungs that are mediated by or result from human neutrophil elastase activity by administering an effective amount of the pharmaceutical aerosol to a subject in need thereof. Representative lung diseases or conditions explicitly include alpha-1 antitrypsin deficiency (AATD), cystic fibrosis (CF), non-cystic fibrosis bronchiactasis (NCFB), and chronic obstructive pulmonary disease (COPD), including pulmonary infections mediated by this activity.
Claims Coverage
The document includes two independent claims directed to methods of treating lung diseases or conditions mediated by human neutrophil elastase activity by administering an effective amount of a pharmaceutical aerosol with specified droplet size characteristics and a dispersed aqueous liquid phase containing the cyclo(-OctG-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Tyr-DPro-Pro-) active compound (or a pharmaceutically acceptable salt). Across these independent claims, the inventive features center on the specific active compound definition, the dispersed liquid/continuous gas aerosol architecture, and quantified droplet size distribution parameters, with claim 1 additionally requiring sodium chloride.
Aerosol-mediated neutrophil elastase inhibition for lung diseases
A method of treating diseases or conditions of the lungs being mediated by or resulting from human neutrophil elastase activity by administering an effective amount of a pharmaceutical composition comprising cyclo(-OctG-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Tyr-DPro-Pro-) or any pharmaceutically acceptable salt thereof to inhibit neutrophil elastase activity in the subject.
Dispersed aqueous liquid phase and continuous gas phase aerosol architecture
Administering the pharmaceutical composition as pharmaceutical aerosol for pulmonary administration comprising a dispersed liquid phase and a continuous gas phase, wherein the dispersed liquid phase comprises aqueous droplets comprising the active compound or any pharmaceutically acceptable salt thereof.
Specified droplet size distribution (MMD and geometrical standard deviation)
The dispersed liquid phase droplets have a mass median diameter from about 1.5 um to about 5 um and a droplet size distribution having a geometrical standard deviation from about 1.2 to about 1.7.
Sodium chloride as a further component
The pharmaceutical composition further comprises sodium chloride.
Across the independent claims, the core claim coverage is the use of an inhalable pharmaceutical aerosol having a dispersed aqueous droplet phase containing cyclo(-OctG-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Tyr-DPro-Pro-) (or a pharmaceutically acceptable salt), together with specified droplet size distribution parameters (mass median diameter and geometrical standard deviation) to inhibit human neutrophil elastase activity for treating lung diseases/conditions mediated by or resulting from that activity. Claim 1 additionally requires sodium chloride.
Stated Advantages
Inhibits neutrophil elastase activity in the subject.
Treats diseases or conditions of the lungs being mediated by or resulting from human neutrophil elastase activity.
Documented Applications
Treatment of lung diseases or conditions mediated by or resulting from human neutrophil elastase activity, including alpha-1 antitrypsin deficiency (AATD), cystic fibrosis (CF), non-cystic fibrosis bronchiactasis (NCFB), and chronic obstructive pulmonary disease (COPD).
Treatment of pulmonary infections in which lung disease/conditions are mediated by human neutrophil elastase activity.
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