Bismuth-thiol compositions and methods of use
The invention relates to Bis-thiol compounds and pharmaceutical preparations thereof. The invention further relates to methods of treating, managing or lessening the severity of pulmonary infections in a subject, the method comprising administering to the subject a bismuth-thiol (BT) composition that comprises at least one BT compound.
1. A method of treating, managing or lessening the severity of cystic fibrosis (CF) symptoms and infections in a subject, the method comprising administering to the subject an aerosol comprising a plurality of dispersed liquid droplets, wherein the liquid droplets comprise a bismuth-thiol (BT) composition that comprises bismuth-1,2-ethanedithiol (BisEDT) microparticles suspended therein, the BisEDT microparticles having a D90 of less than about 2 μm as measured by laser diffraction, and wherein at least 70% of the liquid droplets have a mass median aerodynamic diameter (MMAD) from about 0.4 μm to about 5 μm as measured by cascade impaction or laser time of flight.
2. The method of claim 1 , wherein at least 80% of the dispersed liquid droplets have a MMAD from about 0.7 μm to about 4 μm.
3. The method of claim 1 , wherein at least 90% of the dispersed liquid droplets have a MMAD from about 0.9 μm to about 3 μm.
4. The method of claim 1 , wherein the BT composition comprises BisEDT at a concentration greater than about 0.1 mg/mL, about 0.05% to about 1.0% of polysorbate 80, about 0.05 mM to 40 mM of sodium chloride, and optionally about 2 mM to 20 mM of sodium phosphate at about pH 7.4.
5. The method of claim 1 , wherein when the aerosolized composition comprising BisEDT is deposited to the lung region, the BisEDT has an average half-life of about 4 days.
6. The method of claim 1 , wherein the subject has at least one pulmonary infection containing one or more bacterial pathogens and/or fungal pathogens.
7. The method of claim 6 , wherein the method comprises at least one of: (i) reducing initial formation of a bacterial biofilm; (ii) impairing growth of a bacterial biofilm; (iii) reducing reformation of the bacterial biofilm.
8. The method of claim 6 , wherein the one or more pathogens are selected from Haemophilus influenzae, Staphylococcus aureus, Staphylococcus warneri Staphylococcus lugdunensis, Staphylococcus epidermidis, Streptococcus milleri/anginous, Streptococcus pyogenes , non-tuberculosis mycobacteria, Mycobacterium tuberculosis, Burkholderia spp., Achromobacter xylosoxidans, Stenotrophomonas maltophilia, Alcaligenes xylosoxidans, Haemophilus pittmaniae, Serratia marcescens, Candida albicans , drug resistant Candida albicans, Candida glabrata, Candida krusei, Candida guilliermondii, Candida auris, Candida tropicalis, Aspergillus niger, Aspergillus terreus, Aspergillus fumigatus, Aspergillus flavus, Morganella morganii, Inquilinus limosus, Bdellovibrio bacteriovorus, Vampirovibrio chlorellavorus, Cupriadidus metallidurans, Cupriavidus pauculus, Cupriavidus respiraculi, Exophilia dermatitidis, Herbaspirillum frisingense, Herbaspirillum seropedicae, Neisseria gonorrhoeae , New Delhi metallo-beta-lactamase 1 positive E. coli , Vancomycin-resistant E. faecium , Vancomycin-resistant E. faecalis, E. faecium, E. faecalis , Clindamycin-resistant S. agalactiae, S. agalactiae, Bacteroides fragilis, Clostridium difficile, Streptococcus pneumonia, Moraxella catarrhalis, Haemophilus haemolyticus, Haemophilus parainfluenzae, Chlamydophilia pneumoniae, Mycoplasma pneumoniae, Atopobium, Sphingomonas, Saccharibacteria, Leptotrichia, Capnocytophaga, Oribacterium, Aquabacterium, Lachnoanaerobaculum, Campylobacter, Acinetobacter; Agrobacterium; Bordetella; Brevundimonas; Chryseobacterium; Delftia; Enterobacter; Klebsiella; Pandoraea; Pseudomonas; Ralstonia , and Prevotella.
9. The method of claim 8 , wherein the one or more pathogens are non-tuberculosis mycobacteria.
10. The method of claim 1 , wherein when the aerosolized composition comprising BisEDT is deposited to a lung region, the BisEDT has an average half-life of more than 2 days.
11. A method of treating, managing or lessening the severity of symptoms and infections associated with one or more pulmonary diseases or infections in a subject, the method comprising administering to the subject an aerosol comprising a plurality of dispersed liquid droplets, wherein the liquid droplets comprise a bismuth-thiol (BT) composition that comprises BisEDT microparticles suspended therein, the BisEDT microparticles having a D90 of less than about 2 μm as measured by laser diffraction, and wherein at least 70% of the liquid droplets have a MMAD from about 0.4 μm to about 5 μm as measured by cascade impaction or laser time of flight.
12. The method of claim 11 , wherein the one or more pulmonary diseases or infections are not the result of or associated with cystic fibrosis.
13. The method of claim 12 , wherein the pulmonary infection is bronchiectasis infection, pneumonia, valley fever, allergic bronchopulmonary aspergillosis, ventilator acquired pneumonia, hospital acquired pneumonia, community acquired pneumonia, ventilator associated tracheobronchitis, lower respiratory tract infection, non-tuberculous Mycobacteria (NTM), anthrax, legionellosis, pertussis, bronchitis, Bronchiolitis, chronic obstructive pulmonary disease associated infection, and post-lung transplantation.
14. The method of claim 13 , wherein the pulmonary infection is NTM.
15. The method of claim 8 , wherein
the species of Pseudomonas is selected from the group consisting of Pseudomonas aeruginosa, Pseudomonas mendocina, Pseudomonas pseudoalcaligenes, Pseudomonas putida , and Pseudomonas stutzeri;
the species of Pandoraea is selected from the group consisting of Pandoraea sputorum, Pandoraea apista, Pandoraea pnomenusa, Pandoraea sputorum, Pandoraea norimbergensis , and Pandoraea pulmonicola;
the species of Ralstonia is selected from the group consisting of Ralstonia mannitolilytica, Ralstonia insidiosa , and Ralstonia pickettii;
the species of Acinetobacter is Acinetobacter baumanni;
the species of Bordetella is Bordetella bronchiseptica;
the species of Enterobacter is Enterobacter cloaca;
the species of Klebsiella is Klebsiella pneumoniae ; and
the species of Delftia is Delftia acidivordans.
16. The method of claim 1 , wherein administering the BT composition is via inhalation, orally or nasally, using an aerosol device.
17. The method of claim 1 , wherein upon administration of the aerosolized composition to the subject, at least 15% of the dose is deposited on the lung.
18. The method of claim 1 , wherein upon administration of the aerosolized composition to the subject, at least 60% of the dose is deposited on the lung.
19. The method of claim 11 , wherein upon administration of the aerosolized composition to the subject, at least 15% of the dose is deposited on the lung.
20. The method of claim 11 , wherein upon administration of the aerosolized composition to the subject, at least 60% of the dose is deposited on the lung.
21. The method of claim 11 , wherein at least 80% of the dispersed liquid droplets have a MMAD from about 0.7 μm to about 4 μm.
22. The method of claim 11 , wherein at least 90% of the dispersed liquid droplets have a MMAD from about 0.9 μm to about 3 μm.