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-11235024-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 relates to a pharmaceutical aerosol for pulmonary administration in which an active compound is formulated as a dispersed liquid phase and a continuous gas phase. The dispersed liquid phase comprises aqueous droplets containing cyclo(-OctG-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Tyr-DPro-Pro-) or a pharmaceutically acceptable salt thereof, with OctG defined as (S)-2-aminodecanoic acid and DPro defined as D-proline. The aerosol is characterized by 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 invention further concerns specific aerosol and formulation constraints that enable delivery by a nebulizer, including use of sodium chloride in the aqueous droplets and a liquid pharmaceutical composition concentration of the active compound within a range from about 4 mg/mL to about 100 mg/mL. In embodiments using a solid pharmaceutical composition, the solid composition is dissolvable or dispersible in an aqueous liquid solvent to prepare the liquid composition for pulmonary delivery. The aerosol structure is described as dispersed aqueous droplets in a continuous gas phase.
The invention is presented as a solution to lung diseases or conditions mediated by or resulting from human neutrophil elastase activity in a subject. It addresses the need to prevent, manage, or treat such lung diseases or conditions by delivering the β-hairpin peptidomimetic cyclo(-OctG-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Tyr-DPro-Pro-) as an inhaled liquid aerosol. Nonclinical and clinical evaluations are described, including inhalation studies and measurements of neutrophil elastase activity in sputum.
The disclosed approach is supported with documented aerosol characterization and stability findings, including measured particle size distributions and stability over time. The document describes both preclinical inhalation toxicity and pharmacodynamic effects, including reduced active neutrophil elastase in sputum following administration in first-in-man studies. Together, the formulation and aerosol delivery framework is directed to pulmonary administration of the active compound for diseases mediated by human neutrophil elastase.
Claims Coverage
The document provides one independent claim describing a kit that prepares and delivers a pharmaceutical aerosol for pulmonary administration. The independent claim contains multiple inventive features that jointly define the aerosol structure, droplet composition, aerosol droplet size distribution, active compound concentration range, and kit components, with dependent claims refining nebulizer type, aerosolization rate, droplet fraction constraints, and salt form.
Dispersed liquid phase and continuous gas phase aerosol kit for pulmonary administration
A kit for the preparation and delivery of a pharmaceutical aerosol for pulmonary administration comprising a dispersed liquid phase and a continuous gas phase.
Aqueous droplets containing cyclo(-OctG-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Tyr-DPro-Pro-) (or pharmaceutically acceptable salt) with OctG and DPro definitions
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 pharmaceutically acceptable salt thereof, wherein OctG is (S)-2-aminodecanoic acid and DPro is D-proline.
Aqueous droplets include sodium chloride
The dispersed liquid phase comprises sodium chloride.
Specific droplet mass median diameter range
The dispersed liquid phase has a mass median diameter from about 1.5 µm to about 5 µm.
Specific droplet size distribution geometrical standard deviation range
The dispersed liquid phase has a droplet size distribution having a geometrical standard deviation from about 1.2 to about 1.7.
Nebulizer and liquid composition with active compound concentration 4 mg/mL to 100 mg/mL
The kit comprises a nebulizer and a liquid composition comprising a concentration within a range from about 4 mg/mL to about 100 mg/mL of the active compound, or pharmaceutically acceptable salt thereof.
Solid composition dissolvable or dispersible to form the liquid 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 pharmaceutically acceptable salt thereof and wherein the solid composition is dissolvable or dispersible in an aqueous liquid solvent.
Use for prevention, management or treatment of lung diseases mediated by or resulting from human neutrophil elastase activity
The kit is 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.
Nebulizer type selected from specified nebulizers
The kit comprises a nebulizer selected from jet nebulizers, ultrasonic nebulizers, piezoelectric/electrohydrodynamic/perforated membrane nebulizers, perforated membrane nebulizers, and perforated vibrating membrane nebulizers.
Nebulizer aerosolization rate at least about 0.8 mg/min
The kit includes a nebulizer adapted to aerosolize the liquid composition at a rate of at least about 0.8 mg per minute of the active compound cyclo(-OctG-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Tyr-DPro-Pro-) or pharmaceutically acceptable salt thereof.
Loaded dose droplet fraction with mass median diameter not more than about 5 µm
At least about 70 wt.-% of a loaded dose of the active compound or pharmaceutically acceptable salt thereof is comprised of droplets having a mass median diameter of not more than about 5 µm.
Acetate salt form of the active compound
The kit includes a pharmaceutically acceptable salt form of the active compound wherein the salt is an acetate.
Package insert instructions to treat neutrophil elastase-mediated lung diseases
The kit includes a package insert with instructions to treat a subject’s diseases or conditions of the lungs mediated by or resulting from human neutrophil elastase activity using the active compound.
Across the independent kit claim and its refinements, the main inventive content is directed to pulmonary delivery of cyclo(-OctG-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Tyr-DPro-Pro-) (or acetate salt) in an aerosol with defined droplet size characteristics (MMD 1.5–5 µm; GSD 1.2–1.7), formulated in aqueous droplets including sodium chloride and delivered via a nebulizer at specified concentration and performance constraints, for prevention, management, or treatment of lung diseases mediated by human neutrophil elastase activity.
Stated Advantages
Prevention, management or treatment of diseases or conditions of the lungs mediated by or resulting from human neutrophil elastase activity in a subject.
Reduces active neutrophil elastase in sputum as supported by pharmacodynamics described in first-in-man studies.
Documented Applications
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.
Cystic fibrosis (CF).
Alpha-1 antitrypsin deficiency (AATD).
Non-cystic fibrosis bronchiactasis (NCFB).
Chronic obstructive pulmonary disease (COPD).
Acute respiratory distress syndrome (ARDS).
Ischaemic-reperfusion injury.
Alpha1-proteinase inhibitor (alpha1PI).
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