Tiotropium dry powders
Inventors
Sung, Jean C. • Manzanedo, Diana • PERRY, Jason M. • Dehaan, Wesley • Trautman, Brian
Assignees
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Publication Number
US-9737518-B2
Publication Date
2017-08-22
Expiration Date
Abstract
The present invention relates to respirable dry powder comprising respirable dry particles that comprise sodium chloride, leucine, and tiotropium bromide, wherein the sodium chloride is about 60% to about 90%, the leucine is about 10% to about 40%, the tiotropium bromide is about 0.01% to about 0.5%, and optionally one or more additional therapeutic agents up to about 20%, wherein all percentages are weight percentages on a dry basis and all the components of the respirable dry particles amount to 100%. The invention also relates to respirable dry powders that contain respirable dry particles that comprise sodium chloride, leucine, and tiotropium bromide, wherein the sodium chloride is 67% to 84%, the leucine is 12% to 28%, the tiotropium bromide is about 0.01% to about 0.5%, and optionally one or more additional therapeutic agents up to about 20%, wherein all percentages are weight percentages on a dry basis and all the components of the respirable dry particles amount to 100%. The invention also relates to respirable dry powders that contain respirable dry particles that comprise about 79.5% to about 80.5% (w/w) sodium chloride, about 19.5% to about 20.5% (w/w) leucine, and about 0.01% to about 0.5% (w/w) tiotropium bromide, and methods for treating a subject using the respirable dry powders.
Core Innovation
The invention relates to a receptacle comprising a respirable dry powder formed from homogenous respirable dry particles. The dry particles comprise sodium chloride, leucine, and tiotropium bromide, with sodium chloride present at 67% to 84% by weight, leucine present at 12% to 28% by weight on a dry basis, and tiotropium bromide present at about 0.01% to about 0.5% by weight. The components amount to 100%, and the receptacle contains a nominal dose of tiotropium between about 1.5 to about 12 micrograms or between about 0.5 to about 6 micrograms.
The receptacle optionally includes one or more additional therapeutic agents in an amount up to about 20% by weight, including one or more corticosteroids. The formulation is suitable for respirable dry powder inhalation delivery and passive DPI formats using capsule-based or blister-based receptacles.
The document describes monovalent cation-based dry powder tiotropium bromide formulations, including Formulations I-IV and a specific Formulation II, with clinical and in vitro evidence. The evidence includes improvement in specific airway resistance during methacholine challenge, pilot/Phase Ib PK/PD results in moderate-to-severe COPD, measurable delivery to lungs and bronchodilation as reflected by increased FEV1 at peak and 24 h trough, and aerodynamic particle sizing showing comparable fine particle distributions below 5.0 μm and reduced flow-rate dependence versus SPIRIVA HANDIHALER.
Claims Coverage
The document provides two independent claim positions, both directed to a receptacle with homogeneous respirable dry particles containing sodium chloride, leucine, and tiotropium bromide in specified weight ranges, with optional additional therapeutic agents up to about 20% by weight. The independent claims differ primarily in the nominal tiotropium dose range.
Homogeneous respirable dry particles with sodium chloride, leucine, and tiotropium bromide
A receptacle comprising homogeneous respirable dry particles that comprise sodium chloride, leucine, and tiotropium bromide, wherein sodium chloride is 67% to 84% by weight, leucine is 12% to 28% by weight, and tiotropium bromide is about 0.01% to about 0.5% by weight, with all percentages being weight percentages on a dry basis and all components amounting to 100%.
Optional additional therapeutic agents up to 20% by weight
The receptacle optionally includes one or more additional therapeutic agents up to about 20% by weight, including one or more corticosteroids, with the components of the respirable dry particles amounting to 100% on a dry basis.
Nominal tiotropium dose range
The receptacle contains a nominal dose of tiotropium between about 1.5 to about 12 micrograms, or in another independent claim between about 0.5 to about 6 micrograms.
Across the independent claims, the inventive concept is a homogeneous respirable dry powder in a receptacle comprising sodium chloride, leucine, and tiotropium bromide with defined weight-percentage ranges, optional additional therapeutic agents up to about 20% by weight, and specified nominal tiotropium dose ranges.
Stated Advantages
Improved delivery efficiency versus SPIRIVA HandiHaler, including reduced nominal dose while matching or improving lung function metrics like FEV1.
Maintained tiotropium activity.
Improvement in specific airway resistance during methacholine challenge.
Measurable delivery to lungs in moderate-to-severe COPD with bronchodilation indicated by increased FEV1 at peak and 24 h trough.
Substantially higher delivery efficiency versus SPIRIVA HANDIHALER, indicated by higher fine particle fraction as a percentage of nominal dose.
Reduced flow-rate dependence versus SPIRIVA HANDIHALER for delivery efficiency.
Documented Applications
Respiratory disease treatment including COPD and asthma, including treatment of acute exacerbations.
Passive DPI delivery using capsule-based or blister-based dry powder inhalers.
Clinical evaluation in moderate-to-severe COPD using pilot/Phase Ib PK/PD assessments, including bronchodilation outcomes reflected by FEV1.
In vitro aerodynamic particle sizing using the NGI, comparing Formulation II to SPIRIVA HANDIHALER across relevant flow rates and fine particle distributions.
Methacholine challenge assessment of specific airway resistance during testing versus placebo.
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