Compositions of clofazimine, combinations comprising them, processes for their preparation, uses and methods comprising them
Inventors
Hofmann, Thomas • Ufer, Stefan • Stapleton, Kevin
Assignees
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Publication Number
US-12433889-B2
Publication Date
2025-10-07
Expiration Date
Abstract
The present invention relates to pharmaceutical compositions for inhalation comprising a therapeutically effective dose of clofazimine wherein the clofazimine is provided in the form of a suspension, and processes for their preparation. Furthermore, the present invention provides pharmaceutical combinations comprising clofazimine in the form of an aerosol for pulmonary inhalation. The combinations and compositions provided by the present invention may be used in the treatment and/or prophylaxis of pulmonary infections caused by mycobacteria and other gram-positive bacteria, and of pulmonary fungal infections.
Core Innovation
The invention describes an inhalable pharmaceutical composition that includes clofazimine, provided in a therapeutically effective dose as particles in a suspension. The suspension is formulated with a nonionic surfactant having a hydrophilic-lipophilic balance value greater than 10 and an aqueous liquid carrier selected from water, isotonic saline, buffered saline, and aqueous electrolyte solutions.
The composition further includes a mucolytic and/or biofilm destructing agent. The formulation is intended for pulmonary delivery via aerosol inhalation, where the clofazimine-containing suspension is nebulized to produce inhalation aerosol particles having a mass median aerodynamic diameter of 1 to 5 µm.
A system aspect is described in which a nebulizer is used with the nebulized pharmaceutical combination to provide antibiotic activity in treating or providing prophylaxis against pulmonary infections caused by mycobacteria or other gram-positive bacteria. In this system, clofazimine is present as a suspension in the nebulizer, together with the nonionic surfactant, aqueous liquid carrier, and mucolytic and/or biofilm destructing agent, and the resulting aerosol is characterized by the specified aerodynamic particle size range.
Claims Coverage
The partial content includes two independent claims: one for a pharmaceutical composition and one for a system comprising a nebulized pharmaceutical combination and a nebulizer. Across the independent claims, four inventive features are present: the clofazimine suspension formulation, particle-size constraints for the suspended clofazimine, inclusion of a mucolytic and/or biofilm destructing agent, and a nebulized system that produces aerosol particles with a defined aerodynamic size range.
Clofazimine suspension with nonionic surfactant in aqueous carrier
A pharmaceutical composition comprising a therapeutically effective dose of clofazimine (or a pharmaceutically acceptable derivative or salt thereof) provided in the form of particles in a suspension, a nonionic surfactant having a hydrophilic-lipophilic balance value greater than 10, and an aqueous liquid carrier selected from water, isotonic saline, buffered saline and aqueous electrolyte solutions.
Clofazimine particle size constraints in suspension
The clofazimine (or pharmaceutically acceptable derivative or salt) particles have a median size of less than 5 µm and a D90 of less than 6 µm.
Mucolytic and/or biofilm destructing agent included
The pharmaceutical composition further includes a mucolytic and/or biofilm destructing agent.
Nebulized system for pulmonary antibiotic activity with defined aerosol size
A system for use in providing antibiotic activity when treating or providing prophylaxis against a pulmonary infection caused by mycobacteria or other gram-positive bacteria, comprising a nebulized pharmaceutical combination containing clofazimine, a nonionic surfactant with hydrophilic-lipophilic balance value greater than 10, an aqueous liquid carrier selected from water, isotonic saline, buffered saline and aqueous electrolyte solutions, and a mucolytic and/or biofilm destructing agent, and a nebulizer wherein clofazimine is present in the form of a suspension.
Aerosol aerodynamic particle size range
The system produces aerosol particles having a mass median aerodynamic diameter of 1 to 5 µm.
The claim set in the provided material centers on delivering clofazimine as suspended particles in an aqueous liquid carrier with a nonionic surfactant (HLB>10), optionally in combination with a mucolytic and/or biofilm destructing agent, and enforcing particle-size constraints for both the suspended clofazimine (median <5 µm; D90 <6 µm) and the resulting aerosol (MMAD 1–5 µm) for pulmonary antibiotic activity.
Stated Advantages
Provides antibiotic activity for treating or providing prophylaxis against pulmonary infections caused by mycobacteria or other gram-positive bacteria.
Enables pulmonary delivery via inhalation aerosol characterized by a mass median aerodynamic diameter of 1 to 5 µm.
Uses clofazimine particle-size constraints (median size <5 µm and D90 <6 µm) for the suspension formulation.
Documented Applications
Treating or providing prophylaxis against pulmonary infections caused by mycobacteria or other gram-positive bacteria.
Treatment/prophylaxis of pulmonary mycobacterial infections, including nontuberculous mycobacteria such as M. abscessus and M. avium (MAC), as well as pulmonary fungal infections such as Candida albicans and Aspergillus fumigatus [as described in the provided summary text].
Preclinical evaluation contexts described include acute and chronic mouse infection efficacy and in vitro assessments related to epithelial barrier/inflammation and macrophage uptake, with tolerability described in Balb/C mice [as described in the provided summary text].
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