JPWO2020252462A5 - - Google Patents

Claims (40)

1. An enhancer composition for treating a non-tuberculous mycobacterial ( NTM) infection in a patient, said enhancer composition being administered to the patient's lungs and administering one or more antibiotics to the patient. , an enhancer composition . 4. The enhancer composition comprises one or more metabolites selected from Krebs cycle metabolites, beta-oxidation pathway metabolites, lipid catabolism metabolites, alkanoic acids or alkanoates, and glycerol. 2. The enhancer composition according to 1. 2. The enhancer composition of claim 1, wherein the enhancer composition comprises an aliphatic mono- or dicarboxylic acid, or a salt or ester thereof. 4. The enhancer composition of claim 3, wherein said aliphatic mono- or dicarboxylic acid, or salt or ester thereof, contains up to 16 carbon atoms. 5. The enhancer composition of claim 4, wherein said aliphatic mono- or dicarboxylic acid, or salt or ester thereof, contains up to 10 carbon atoms. 5. The enhancer composition of claim 4, wherein said fatty mono- or dicarboxylic acid is a straight or branched chain fatty acid, or a salt or ester thereof. 7. The enhancer of claim 6, wherein said straight or branched chain fatty acid is a short chain fatty acid, or salt or ester thereof, and said short chain fatty acid, or salt or ester thereof, is optionally an alkyl ester. composition . The enhancer composition comprises propanoic acid, or salts or esters thereof; butanoic acid, or salts or esters thereof; 2-methylpropanoic acid, or salts or esters thereof; pentanoic acid, or salts or esters thereof; 3-methylbutanoic acid, or salts or esters thereof; caproic acid, 4-methylpentanoic acid, or salts or esters thereof; sebacic acid, or salts or esters thereof; and pyruvic acid, or salts or esters thereof 2. The enhancer composition of claim 1, comprising one or more of: The enhancer composition of any one of claims 1-8, wherein the enhancer composition comprises glycerol. The enhancer composition of any one of claims 1-9, wherein the enhancer composition is administered as a powder or aerosol for inhalation. 11. The enhancer composition of claim 10, wherein the enhancer composition is administered by a nebulizer. 12. The enhancer composition of claim 11, wherein said enhancer composition comprises liposomes. The enhancing agent of any one of claims 1-12, wherein the patient is administered one or more antibiotics selected from aminoglycoside antibiotics, macrolide antibiotics, ethambutol, and rifamycin. composition . amikacin, streptomycin, tobramycin, apramycin, arbekacin, astromycin, capreomycin, dibekacin, framycetin, gentamicin, hygromycin B, isepamycin, kanamycin, neomycin, netilmicin, paromomycin, rhodestreptomycin, ribostamycin, sisomycin, speck 14. The enhancer composition of claim 13, wherein an aminoglycoside antibiotic selected from tinomycin and verdamycin, or a pharmaceutically acceptable salt thereof, is administered. 15. The enhancer composition of claim 14, wherein the patient is administered amikacin or streptomycin or a pharmaceutically acceptable salt thereof. 16. The enhancer composition of claim 14 or 15, wherein the aminoglycoside antibiotic is administered locally to the lung. 17. The enhancer composition of claim 16, wherein said aminoglycoside antibiotic is in the form of an aqueous solution or suspension administered by nebulizer. 18. The enhancer composition of claim 17 , wherein said aminoglycoside antibiotic is in the form of a liposomal formulation. The enhancer composition of any one of claims 16-18, wherein said aminoglycoside antibiotic is co-formulated in said enhancer composition . The enhancer composition of any one of claims 13-19, wherein the patient is administered a macrolide antibiotic. The macrolide antibiotic is azithromycin, clarithromycin, erythromycin, fidaxomycin, carbomycin A, josamycin, kitasamycin, midecamycin acetate, oleandomycin, sorithromycin, spiramycin, troleandomycin, tylosin ( 21. The enhancer composition of claim 20, selected from tylosin, tylocine, and roxithromycin or pharmaceutically acceptable salts thereof. 22. The enhancer composition of claim 21, wherein said macrolide antibiotic is administered orally. The enhancer composition of any one of claims 13-22, wherein the patient is administered rifampin or rifabutin. 24. The enhancer composition of claim 23, wherein said rifampin is administered orally. The enhancer composition of any one of claims 13-24, wherein the patient is administered ethambutol. 26. The enhancer composition of claim 25, wherein said ethambutol is administered orally. For said non-tuberculous mycobacterial infections, M. avium, M. avium subsp. hominissuis (MAH), M. abscessus, M. chelonae, M. bolletii, M. kansasii, M.; ulcerans, M. avium complex (MAC) (M. avium and M. intracellulare), M. chimaera, M. conspicuum, M. peregrinum, M. Immunogenum, M. xenopi, M. marinum, M. malmoense, M.; mucogenicum, M. nonchromogenicum, M. scrofulaceum, M. simae, M. smegmatis, M. szulgai, M.; terrae, M. terrae complex, M. haemophilum, M. genavense, M.; gordonae, M. fortuitum, M. 27. The enhancer composition of any one of claims 1-26 involving a fortuitum complex (M. fortuitum and M. chelonae), or a combination thereof. 28. The enhancer composition of any one of claims 1-27, wherein the enhancer composition is administered at least three times per week. 29. The enhancer composition of claim 28, wherein the enhancer composition is administered once or twice weekly. 30. The enhancer composition of claim 28 or 29, wherein said administration period is for at least 6 months. 31. The enhancer composition of claim 30, wherein said administration period is at least 12 months, or at least 18 months. 31. The enhancer composition of claim 30, wherein said administration period is less than 1 year. A unit dose formulation for administration by a nebulizer comprising 100-600 mg of an aminoglycoside antibiotic or salt thereof and an amount of an aliphatic monoglycoside effective to enhance aminoglycoside activity against non-tuberculous mycobacterium (NTM). or dicarboxylic acids, or salts or esters thereof. 34. A unit dose according to claim 33, wherein said aliphatic mono- or dicarboxylic acid, or salt or ester thereof, contains up to 16 carbon atoms. 35. A unit dose according to claim 34, wherein said aliphatic mono- or dicarboxylic acid, or salt or ester thereof, contains up to 10 carbon atoms. 35. A unit dose according to claim 34, wherein said aliphatic mono- or dicarboxylic acid is a straight or branched chain fatty acid, or a salt or ester thereof. 37. The unit dose of Claim 36, wherein said straight or branched chain fatty acid is a short chain fatty acid, or a salt or ester thereof. The aliphatic mono- or dicarboxylic acid is propanoic acid, or a salt or ester thereof; butanoic acid, or a salt or ester thereof; 2-methylpropanoic acid, or a salt or ester thereof; pentanoic acid, or a salt or ester thereof Esters; 3-methylbutanoic acid, or salts or esters thereof; caproic acid, 4-methylpentanoic acid, or salts or esters thereof; sebacic acid, or salts or esters thereof; and pyruvic acid, or salts or esters thereof 34. The unit dose of claim 33, comprising one or more of A unit dose according to any one of claims 33-38, further comprising glycerol. 40. The unit dose of any one of claims 33-39, wherein said aminoglycoside antibiotic is amikacin, and said amikacin is contained in a liposome with said aliphatic mono- or dicarboxylic acid, or salt or ester thereof. .