Respirably dry powder comprising calcium lactate, sodium chloride and leucine
Inventors
Lipp, Michael M. • Sung, Jean C.
Assignees
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Publication Number
US-8758824-B2
Publication Date
2014-06-24
Expiration Date
Abstract
The present invention relates to respirable dry powders that contain respirable dry particles that comprise about 20% (w/w) leucine, about 75% (w/w) calcium lactate, and about 5% (w/w) sodium chloride, or about 37.5% (w/w) leucine, about 58.6% (w/w) calcium lactate, and about 3.9% (w/w) sodium chloride, and methods for treating a subject using the respirable dry powders.
Core Innovation
The invention relates to a respirable dry powder comprising respirable dry particles that comprise specified dry-basis amounts of leucine, calcium lactate, and sodium chloride. The disclosed composition provides alternative leucine/calcium lactate/sodium chloride sets that define the dry particle makeup for inhalable delivery. The formulation is characterized in terms of aerosol and solid-state properties relevant to delivery, including amorphous/crystalline phase behavior and particle and powder performance parameters.
The respirable dry powder is characterized by particle and powder performance parameters including fine particle fraction, volume median geometric diameter measured on HELOS/RODOS at a one bar dispersion setting, Hausner ratio thresholds, dispersibility ratios at multiple regulator pressures, and capsule emitted powder mass. Emitted dose and CEPM performance are associated with a total inhalation energy threshold of less than about 1 Joule, and aerodynamic sizing is also described using Andersen cascade impactor. The disclosed work addresses formulation and manufacturing from aqueous feedstock by spray drying.
The document further connects composition and delivery-relevant particle properties to in vitro and in vivo performance. Reported outcomes include reduced airway inflammation and eosinophilia in a mouse OVA allergic asthma model, reductions in viral titers and fever/weight effects in a ferret influenza model, reductions in inflammatory cells and inflammatory chemokines KC and MIP2 in COPD tobacco smoke models, reduced lung bacterial burden in a mouse bacterial pneumonia model, and efficacy in other disease models described in the document.
Claims Coverage
The independent claim coverage centers on a respirable dry powder with two alternative specified leucine, calcium lactate, and sodium chloride composition sets. Dependent claims further refine the formulation and delivery performance using quantitative particle-powder metrics and optional therapeutic-agent selections, and they recite treatment or prevention by administration to a patient’s respiratory tract.
Specified leucine, calcium lactate, and sodium chloride composition
A respirable dry powder comprising respirable dry particles that comprise on a dry basis about 20% (w/w) leucine, about 75% (w/w) calcium lactate, and about 5% (w/w) sodium chloride; or about 37.5% (w/w) leucine, about 58.6% (w/w) calcium lactate, and about 3.9% (w/w) sodium chloride.
Fine particle fraction at less than 3.4 microns
The respirable dry powder has a Fine Particle Fraction (FPF) of less than 3.4 microns of at least 20%.
Volume median geometric diameter at one bar HELOS/RODOS setting
The respirable dry powder particles have a volume median geometric diameter (VMGD) of 5 microns or less as measured at the one bar dispersion setting on the HELOS/RODOS laser diffraction system.
Hausner ratio minimum
The respirable dry powder has a Hausner ratio of at least 1.4.
CEPM achieved under total inhalation energy less than 1 Joule
A Capsule Emitted Powder Mass (CEPM) of at least about 80% of said respirable dry powder contained in a unit dose container is achieved when a total inhalation energy of less than about 1 Joule is applied.
Optional therapeutic agent identities within the formulation
The formulation specifies drug identities: the LABA is formoterol or salmeterol or combinations, the short-acting beta agonist is albuterol, the corticosteroid is fluticasone, the LAMA is tiotropium, and the antibiotic is levofloxacin.
Overall, the claim set is centered on a respirable dry powder defined by specific leucine, calcium lactate, and sodium chloride dry-basis compositions, with dependent claim coverage that further limits aerosol performance and delivery performance, and that optionally specifies particular therapeutic-agent identities and recites treating and/or preventing respiratory diseases by administration to a patient’s respiratory tract.
Stated Advantages
Reduced airway inflammation and eosinophilia in a mouse OVA allergic asthma model when varying Ca:Na ratios, including a 4:1 ratio.
Achievement of high CEPM, at least about 80%, associated with applying a total inhalation energy of less than about 1 Joule.
Documented Applications
Treating and/or preventing respiratory diseases by administering the respirable dry powder to a patient’s respiratory tract, including asthma and infections.
Use of the formulation in a mouse OVA allergic asthma model to assess airway inflammation and eosinophilia.
Use in a ferret influenza model, a COPD tobacco smoke model, and a mouse bacterial pneumonia model.
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