Compositions of bedaquiline, combinations comprising them, processes for their preparation, uses and methods of treatment comprising them

Abstract

To provide compositions of bedaquiline in which formulation agents for bedaquiline having low solubility in water are solubilized and stabilized in liquid aqueous carriers, combinations comprising them, processes for their preparation, uses and methods of treatment comprising them.SOLUTION: The present invention relates to pharmaceutical compositions for inhalation comprising a therapeutically effective dose of bedaquiline wherein the bedaquiline is provided in the form of a suspension, or in which the bedaquiline is provided in the form of a dry powder, and processes for their preparation. Furthermore, the present invention provides pharmaceutical combinations comprising bedaquiline 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.SELECTED DRAWING: None

Description

Technical Field

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 778,953, filed on Dec. 13, 2018, the content of which is incorporated herein by reference. The content thereof is incorporated herein by reference.

[0002] The present invention relates to an inhalation pharmaceutical composition containing bedaquiline in a therapeutically effective amount, provided in the form of a suspension or as a dry powder; methods for preparing them; and uses and treatment methods comprising them. Further, the present invention provides a pharmaceutical combination comprising bedaquiline 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 prevention of lung infections caused by mycobacteria and other Gram-positive bacteria. The combinations and compositions provided by the present invention may be used in the treatment and / or prevention of lung infections caused by mycobacteria and other Gram-positive bacteria. The combinations and compositions provided by the present invention may be used in the treatment and / or prevention of lung infections caused by mycobacteria and other Gram-positive bacteria.

[0003] The combinations and compositions provided by the present invention may be used in the treatment and / or prevention of lung infections caused by mycobacteria and other Gram-positive bacteria. The combinations and compositions provided by the present invention may be used in the treatment and / or prevention of lung infections caused by mycobacteria and other Gram-positive bacteria. The combinations and compositions provided by the present invention may be used in the treatment and / or prevention of lung infections caused by mycobacteria and other Gram-positive bacteria.

Background Art

[0004] Janssen Pharmaceutica (a subsidiary of J&J) began screening for compounds that would kill Mycobacterium smegmatis, a distant relative of Mycobacterium tuberculosis, around 2002, and discovered bedaquiline (initially designated TMC207). Bedaquiline (BDQ) emerged from a whole-cell screen of 70,000 library compounds against a non-pathogenic Mycobacterium smegmatis (M. smegmatis) strain of TB (for example, Guillemont, J., Meyer, C., Poncelet, A., Bourdrez, X. and Andries, K., “Diarylquino a distant relative of Mycobacterium tuberculosis and discovered bedaquiline (initially designated TMC207). Bedaquiline (BDQ) emerged from a whole-cell screen of 70,000 library compounds against a non-pathogenic Mycobacterium smegmatis (M. smegmatis) strain of TB (for example, Guillemont, J., Meyer, C., Poncelet, A., Bourdrez, X. and Andries, K., “Diarylquino and discovered bedaquiline (initially designated TMC207). Bedaquiline (BDQ) emerged from a whole-cell screen of 70,000 library compounds against a non-pathogenic Mycobacterium smegmatis (M. smegmatis) strain of TB (for example, Guillemont, J., Meyer, C., Poncelet, A., Bourdrez, X. and Andries, K., “Diarylquino and discovered bedaquiline (initially designated TMC207). Bedaquiline (BDQ) emerged from a whole-cell screen of 70,000 library compounds against a non-pathogenic Mycobacterium smegmatis (M. smegmatis) strain of TB (for example, Guillemont, J., Meyer, C., Poncelet, A., Bourdrez, X. and Andries, K., “Diarylquino and discovered bedaquiline (initially designated TMC207). Bedaquiline (BDQ) emerged from a whole-cell screen of 70,000 library compounds against a non-pathogenic Mycobacterium smegmatis (M. smegmatis) strain of TB (for example, Guillemont, J., Meyer, C., Poncelet, A., Bourdrez, X. and Andries, K., “Diarylquino .,Bourdrez,X.and Andries,K.,“Diarylquino .,Bourdrez,X.and Andries,K.,“Diarylquino lines, synthesis pathways and quantitativ e structure - activity relationship studie s leading to the discovery of TMC207”, Fu ture Medicinal Chemistry(2011), 3: pp. 1345 - 1360 (see, e.g., Structure - based Medicinal Chemistry (2011), 3: pp. 1345 - 1360), where a racemic mixture (including four diastereomers) was shown to have useful activity against both Mycobacterium smegmatis and Mycobacterium tuberculosis, and the R, S enantiomers were the most potent. Bedaquiline (commercially available under the trademark Sirturo™) belongs to a class of compounds known as diarylquinolines (DARQs), also referred to as substituted quinoline derivatives.

[0005] The chemical names for bedaquiline are · 3 - Quinolineethanol, 6 - bromo - α - [2 - (dimethylamino)ethyl] - 2 - methoxy - α - 1 - naphthalenyl - β - phenyl -, (αS,βR) - ; and · (1R,2S) - 1 - (6 - bromo - 2 - methoxyquinolin - 3 - yl) - 4 - (di methylamino) - 2 - (naphthalen - 1 - yl) - 1 - phenylbutan - 2 - ol and include.

[0006] The structure of bedaquiline (BDQ) is shown below. [Chemical Structure]

[0007] Structurally and mechanistically, DARQs are distinct from fluoroquinolones (including methoxyquinolines) and other different from both quinoline classes (e.g., Andries, K., Verhassel t, P., Guillemont, J., Goehlmann, HWH., Neefs, JM., Winkler, H., Van Gestel, J., Timmerman, P ., Zhu, M., Lee, E., Williams, P., de Chaffoy, D ., Huitric, E., Hoffner, S., Cambau, E., Truffo t-Pernot, C., Lounis, N. and Jarlier, V., “A d iarylquinoline drug active on the ATP sy nthase of Mycobacterium tuberculosis”, Sc ience (2005), 307: pp.223-227). In in vitro tests it has been shown that bedaquiline provides a new mechanism of antituberculosis action by specifically inhibiting mycobacterial adenosine triphosphate (ATP) synthase.

[0008] Bedaquiline is also very lipophilic (logP 7.25 was measured) and may contribute to the induction of phospholipidosis, which is seen at high doses in preclinical models ( e.g., Mesens, N., Verbeeck, J., Rouan, M. and Va nparys, P., “Elucidating the role of M2 in the preclinical safety profile of TMC20 7. In Abstract on the 38th Union World Co nference on Lung Health, Cape Town, South Africa, 2006, Abstract P4-07). See Africa, 2007). Its high lipophilicity may contribute to the long terminal elimination half-life of bedaquiline (e.g., see Svensson, EM., Murray, S., Ka rlsson, MO. and Dooley, KE., “Rifampicin and rifapentine significantly reduce concen trations of bedaquiline, a new anti-TB dr ug”, Journal of Antimicrobial Chemotherap y (2015), 70: pp. 1106-1114), and may lead to disproportionate accumulation in tissues at high doses or with once-daily dosing. More significantly, bedaquiline has been shown to potentially inhibit drug-susceptible tuberculosis, multi-drug resistant tuberculosis and latent tuberculosis, and is the first drug to be approved by the Food and Drug Admins tration for tuberculosis treatment in 40 years. Impressive Phase IIb clinical trials have demonstrated that the addition of bedaquiline to tuberculosis treatment regimens significantly improves cure rates, reduces relapse rates, and decreases the duration of treatment compared to standard regimens alone (e.g., see Diacon, AH., Pym, A., Grobusch , M., Patientia, R., Rustomjee, R., Page-Shipp

[0009] , L., Pistorius, C., Krause, R., Bogoshi, M., Ch urchyard, G., Venter, A., Allen, J., Palomino, JC., De Marez, T., van Heeswijk, RPG., Lounis , M., Patientia, R., Rustomjee, R., Page-Shipp , L., Pistorius, C., Krause, R., Bogoshi, M., Ch urchyard, G., Venter, A., Allen, J., Palomino, JC., De Marez, T., van Heeswijk, RPG., Lounis ,N., Meyvisch, P., Verbeeck, J., Parys, W., de Beule, K., Andries, K. and Mc Neeley, D.F., “Th e Diarylquinoline TMC207 for Multidrug-R esistant Tuberculosis”, The New England J ournal of Medicine(2009), 360: pp.2397-240 5; Diacon, A.H., Dawson, R., von Groote-Bidlin gmaier, F., Symons, G., Venter, A., Donald, P.R. , van Niekerk, C., Everitt, D., Winter, H., Bec ker, P., Mendel, C.M. and Spigelman, M.K., “14-d ay bactericidal activity of PA-824, bedaq uiline, pyrazinamide, and moxifloxacin com binations: a randomised trial”, The Lancet (2012), 380(9846): pp.986-993; Pym, A.S., Diac on, A.H., Tang, S.J., Conradie, F., Danilovits, M ., Chuchottaworn, C., Vasilyeva, I., Andries, K., Bakare, N., De Marez, T., Haxaire-Theeuwe s, M., Lounis, N., Meyvisch, P., Van Baelen, B. , van Heeswijk, R.P.G. and Dannemann, B., “Beda quiline in the treatment of multidrug-an extensively drug-resistant tuberculosis ”,The European Respiratory Journal(2016) ,see 47(2):pp.564-574). Importantly, BDR retains clinical activity against drug-sensitive , multidrug-resistant, and extensively drug-resistant TB.

[0010] The antibacterial activity of bedaquiline (Soni, I., De Groote, M. A., Dasgu pta, A. and Chopra, S., “Challenges facing t he drug discovery pipeline for non-tuber culous mycobacteria”, Journal of Medical Microbiology(2016), 65:pp.1-8) is unique among antibiotics because of its specificity and potency against mycobacteria alone, by inhibiting mycobacterial ATP synthase (Koul, A ., Dendouga, N., Vergauwen, K., Molenberghs, B ., Vranckx, L., Willebrords, R., Ristic, Z., Li ll, H., Dorange, I., Guillemont, J., Bald, D. an d Andries, K., “Diarylquinolines target su bunit c of mycobacterial ATP synthase”, N ature Chemical Biology(2007), 3:pp.323-32 4). Indeed, Andries et al. reported that the minimum inhibitory concentration (MIC99) of bedaquiline was ​Irrespective of resistance to other commonly used anti-TB drugs, it was shown to be between 0.01 and 0.1 μg / ml against various Mycobacterium tuberculosis isolates (Andries, K., Verhasselt, P., Guillemont, J., Goehlmann, HWH., Neefs, JM., Winnkler, H., Van Gestel, J., Timmerman, P., Zhu, M., Lee, E., Williams, P., de Chaffoy, D., Huitric, E., Hoffner, S., Cambau, E., Truffot-Pernot, C., Lounis, N. and Jarlier, V., “A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis”, Science (2005), 307: pp. 223-227). These results were reproduced using a standardized broth dilution assay, and the demonstrated MIC99 was in the range of 0.015 to 0.12 μg / ml against Mycobacterium tuberculosis H37Rv (Kaniga, K., Cirillo, DM., Hoffner, S., Ismail, NA., Kaur, D., Lounis, N., Metchock, B., Pfyffer, GE. and Venter, A.,”A Multilaboratory, Multicountry Study To Determine Bedaquiline MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testi cterium tuberculosis) isolates (Andries, K., Verhasselt, P., Guillemont, J., Goehlmann, HWH., Neefs, JM., Winnkler, H., Van Gestel, J., Timmerman, P., Zhu, M., Lee, E., Williams, P., de Chaffoy, D., Huitric, E., Hoffner, S., Cambau, E., Truffot-Pernot, C., Lounis, N. and Jarlier, V., “A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis”, Science (2005), 307: pp. 223-227). These results were reproduced using a standardized broth dilution assay, and the demonstrated MIC99 was in the range of 0.015 to 0.12 μg / ml against Mycobacterium tuberculosis H37Rv (Kaniga, K., Cirillo, DM., Hoffner, S., Ismail, NA., Kaur, D., Lounis, N., Metchock, B., Pfyffer, GE. and Venter, A.,”A Multilaboratory, Multicountry Study To Determine Bedaquiline MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testi l of Mycobacterium tuberculosis isolates (Andries, K., Verhasselt, P., Guillemont, J., Goehlmann, HWH., Neefs, JM., Winnkler, H., Van Gestel, J., Timmerman, P., Zhu, M., Lee, E., Williams, P., de Chaffoy, D., Huitric, E., Hoffner, S., Cambau, E., Truffot-Pernot, C., Lounis, N. and Jarlier, V., “A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis”, Science (2005), 307: pp. 223-227). These results were reproduced using a standardized broth dilution assay, and the demonstrated MIC99 was in the range of 0.015 to 0.12 μg / ml against Mycobacterium tuberculosis H37Rv (Kaniga, K., Cirillo, DM., Hoffner, S., Ismail, NA., Kaur, D., Lounis, N., Metchock, B., Pfyffer, GE. and Venter, A.,”A Multilaboratory, Multicountry Study To Determine Bedaquiline MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testi illemont, J., Goehlmann, HWH., Neefs, JM., Winnkler, H., Van Gestel, J., Timmerman, P., Zhu, M., Lee, E., Williams, P., de Chaffoy, D., Huitric, E., Hoffner, S., Cambau, E., Truffot-Pernot, C., Lounis, N. and Jarlier, V., “A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis”, Science (2005), 307: pp. 223-227). These results were reproduced using a standardized broth dilution assay, and the demonstrated MIC99 was in the range of 0.015 to 0.12 μg / ml against Mycobacterium tuberculosis H37Rv (Kaniga, K., Cirillo, DM., Hoffner, S., Ismail, NA., Kaur, D., Lounis, N., Metchock, B., Pfyffer, GE. and Venter, A.,”A Multilaboratory, Multicountry Study To Determine Bedaquiline MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testi kler, H., Van Gestel, J., Timmerman, P., Zhu, M., Lee, E., Williams, P., de Chaffoy, D., Huitric, E., Hoffner, S., Cambau, E., Truffot-Pernot, C., Lounis, N. and Jarlier, V., “A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis”, Science (2005), 307: pp. 223-227). These results were reproduced using a standardized broth dilution assay, and the demonstrated MIC99 was in the range of 0.015 to 0.12 μg / ml against Mycobacterium tuberculosis H37Rv (Kaniga, K., Cirillo, DM., Hoffner, S., Ismail, NA., Kaur, D., Lounis, N., Metchock, B., Pfyffer, GE. and Venter, A.,”A Multilaboratory, Multicountry Study To Determine Bedaquiline MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testi ., Lee, E., Williams, P., de Chaffoy, D., Huitric, E., Hoffner, S., Cambau, E., Truffot-Pernot, C., Lounis, N. and Jarlier, V., “A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis”, Science (2005), 307: pp. 223-227). These results were reproduced using a standardized broth dilution assay, and the demonstrated MIC99 was in the range of 0.015 to 0.12 μg / ml against Mycobacterium tuberculosis H37Rv (Kaniga, K., Cirillo, DM., Hoffner, S., Ismail, NA., Kaur, D., Lounis, N., Metchock, B., Pfyffer, GE. and Venter, A.,”A Multilaboratory, Multicountry Study To Determine Bedaquiline MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testi ic, E., Hoffner, S., Cambau, E., Truffot-Pernot, C., Lounis, N. and Jarlier, V., “A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis”, Science (2005), 307: pp. 223-227). These results were reproduced using a standardized broth dilution assay, and the demonstrated MIC99 was in the range of 0.015 to 0.12 μg / ml against Mycobacterium tuberculosis H37Rv (Kaniga, K., Cirillo, DM., Hoffner, S., Ismail, NA., Kaur, D., Lounis, N., Metchock, B., Pfyffer, GE. and Venter, A.,”A Multilaboratory, Multicountry Study To Determine Bedaquiline MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testi t, C., Lounis, N. and Jarlier, V., “A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis”, Science (2005), 307: pp. 223-227). These results were reproduced using a standardized broth dilution assay, and the demonstrated MIC99 was in the range of 0.015 to 0.12 μg / ml against Mycobacterium tuberculosis H37Rv (Kaniga, K., Cirillo, DM., Hoffner, S., Ismail, NA., Kaur, D., Lounis, N., Metchock, B., Pfyffer, GE. and Venter, A.,”A Multilaboratory, Multicountry Study To Determine Bedaquiline MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testi inoline drug active on the ATP synthase of Mycobacterium tuberculosis”, Science (2005), 307: pp. 223-227). These results were reproduced using a standardized broth dilution assay, and the demonstrated MIC99 was in the range of 0.015 to 0.12 μg / ml against Mycobacterium tuberculosis H37Rv (Kaniga, K., Cirillo, DM., Hoffner, S., Ismail, NA., Kaur, D., Lounis, N., Metchock, B., Pfyffer, GE. and Venter, A.,”A Multilaboratory, Multicountry Study To Determine Bedaquiline MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testi of Mycobacterium tuberculosis”, Science (2005), 307: pp. 223-227). These results were reproduced using a standardized broth dilution assay, and the demonstrated MIC99 was in the range of 0.015 to 0.12 μg / ml against Mycobacterium tuberculosis H37Rv (Kaniga, K., Cirillo, DM., Hoffner, S., Ismail, NA., Kaur, D., Lounis, N., Metchock, B., Pfyffer, GE. and Venter, A.,”A Multilaboratory, Multicountry Study To Determine Bedaquiline MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testi 005), 307: pp. 223-227. These results were reproduced using a standardized broth dilution assay, and the demonstrated MIC99 was in the range of 0.015 to 0.12 μg / ml against Mycobacterium tuberculosis H37Rv (Kaniga, K., Cirillo, DM., Hoffner, S., Ismail, NA., Kaur, D., Lounis, N., Metchock, B., Pfyffer, GE. and Venter, A.,”A Multilaboratory, Multicountry Study To Determine Bedaquiline MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testi assay, and the demonstrated MIC99 was in the range of 0.015 to 0.12 μg / ml against Mycobacterium tuberculosis H37Rv (Kaniga, K., Cirillo, DM., Hoffner, S., Ismail, NA., Kaur, D., Lounis, N., Metchock, B., Pfyffer, GE. and Venter, A.,”A Multilaboratory, Multicountry Study To Determine Bedaquiline MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testi rium tuberculosis) H37Rv (Kaniga, K., Cirillo, DM., Hoffner, S., Ismail, NA., Kaur, D., Lounis, N., Metchock, B., Pfyffer, GE. and Venter, A.,”A Multilaboratory, Multicountry Study To Determine Bedaquiline MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testi ml of Mycobacterium tuberculosis) H37Rv (Kaniga, K., Cirillo, DM., Hoffner, S., Ismail, NA., Kaur, D., Lounis, N., Metchock, B., Pfyffer, GE. and Venter, A.,”A Multilaboratory, Multicountry Study To Determine Bedaquiline MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testi , S., Ismail, NA., Kaur, D., Lounis, N., Metchock, B., Pfyffer, GE. and Venter, A.,”A Multilaboratory, Multicountry Study To Determine Bedaquiline MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testi k, B., Pfyffer, GE. and Venter, A.,”A Multilaboratory, Multicountry Study To Determine Bedaquiline MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testi boratory, Multicountry Study To Determine Bedaquiline MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testi Bedaquiline MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testi for Phenotypic Drug Susceptibility Testi ng", Journal of Clinical Microbiology (201 6), 54(12): pp. 2956 - 2962. Interestingly, this activity is present in both M. avium and M. abscessus (M IC99 values are 0.01 - 0.03 μg / ml and 0.25 - 0.5 μg / ml respectively) and extends to other mycobacteria. This activity has been translated to an in vivo model, where bacterial clearance is improved in models of M. tuberculosis and M. abscessus infections (Obregon - Henao, A., Arnett, KA., Henao - Tamay o, M., Massoudi, L., Creissen, E., Andries, K., Lenaerts, AJ. And Ordway, DJ., "Susceptibili ty of Mycobacterium abscessus to Antimyc obacterial Drugs in Preclinical Models", Antimicrobial Agents and Chemotherapy (20 15), 59(11): pp. 6904 - 6912; Tasneen, R., Li, SY ., Peloquin, CA., Taylor, D., Williams, KN., An dries, K., Mdluli, KE. and Nuermberger, EL., " Sterilizing Activity of Novel TMC207 - an d PA - 824 - Containing Regimens in a Murine "Model of Tuberculosis", Antimicrobial Ag ents and Chemotherapy(2011), 55(12); pp.54 85 - 5492). Furthermore, the sterilizing activity of BDQ can act synergistically with a very large number of anti - TB drugs, such as ethambutol, pyrazinamide, linezolid, and clofazimine( Obregon - Henao, A., Arnett, KA., Henao - Tamayo , M., Massoudi, L., Creissen, E., Andries, K., L enaerts, AJ. And Ordway, DJ., "Susceptibilit y of Mycobacterium abscessus to Antimyco bacterial Drugs in Preclinical Models", A ntimicrobial Agents and Chemotherapy(201 5), 59(11): pp.6904 - 6912; Reddy, VM., Einck, L ., Andries, K. and Nacy, CA., "In Vitro Inter actions between New Antitubercular Drug Candidates SQ109 and TMC207", Antimicrobi al Agents and Chemotherapy(2010), 54(7): p p.2840 - 2846; Tasneen, R., Williams, K., Amoab eng, O., Minkowski, A., Mdluli, KE., Upton, AM. and Nuermberger, EL., "Contribution of the Nitroimidazoles PA - 824 and TBA - 354 to t The Activity of Novel Regimens in Murine Models of Tuberculosis”, Antimicrobial Ag ents and Chemotherapy(2015), 59(1): pp.129 -135; Lamprecht, D.A., Finin, P.M., Rahman, A., C umming, B.M., Russell, S.L., Jonnala, S.R., Adams on, J.H. and Steyn, A.J.C., “Turning the respir atory flexibility of Mycobacterium tuber culosis against itself”, Nature Communica tions(2016): DOI:10.1038 / ncomms123。

[0011] Table 1 shows the MIC values (μg / ml) of bedaquiline against different Mycobacteria (Soni, I., De Groote, M.A., Das gupta, A. and Chopra, S., “Challenges facing the drug discovery pipeline for non-tub erculous mycobacteria”, Journal of Medica l Microbiology(2016), 65: pp.1-8).

[0012]

Table 1

[0013] Currently, BDQ is administered orally and here it reaches its maximum plasma concentration 4 - 6 hours after administration. ​(Andries, K., Verhasselt, P., Guillemont, J. , Goehlmann, HWH., Neefs, JM., Winkler, H., Van Gestel, J., Timmerman, P., Zhu, M., Lee, E., Wi lliams, P., de Chaffoy, D., Huitric, E., Hoffn er, S., Cambau, E., Truffot-Pernot, C., Lounis , N. and Jarlier, V., “A diarylquinoline dru g active on the ATP synthase of Mycobact erium tuberculosis”, Science(2005), 307: pp .223 - 227). These serum concentrations are proportional to the dose, and the biological activity of BDQ is concentration-dependent, and the area under the curve (AUC) measurements are the main predictive variables of drug efficacy (R ouan, MC., Lounis, N., Gevers, T., Dillen, L., G ilissen, R., Raoof, A. and Andries, K., “Pharm acokinetics and Pharmacodynamics of TMC2 07 and Its N-Desmethyl Metabolite in a M urine Model of Tuberculosis”, Antimicrobi al Agents and Chemotherapy(2012), 56(3): p p.1444 - 1451). Food intake with BDQ improves bioavailability and has been shown to increase the drug AUC 2 - to 4-fold compared to fasting (Diacon , AH., Pym, A., Grobusch, M., Patientia, R., Rus tomjee, R., Page-Shipp, L., Pistorius, C., Kra use, R., Bogoshi, M., Churchyard, G., Venter, A ., Allen, J., Palomino, JC., De Marez, T., van Heeswijk, RPG., Lounis, N., Meyvisch, P., Verb eeck, J., Parys, W., de Beule, K., Andries, K.a nd Mc Neeley, DF., “The Diarylquinoline TM C207 for Multidrug-Resistant Tuberculosi s”, The New England Journal of Medicine(2 009), 360: pp.2397-2405; van Heeswijk, RPG., Dannemann, B. and Hoetelmans, RMW., “Bedaqui line: a review of human pharmacokinetics and drug-drug interactions”, Journal of A ntimicrobial Chemotherapy(2014), 69: pp.23 10-2318).

[0014] Upon administration, bedaquiline shows preferential tissue accumulation in the lungs and spleen, as well as high binding to plasma proteins in serum (Andries, K., Verhasselt, P., Guillemont, J., Goehlmann, HWH., Neefs, JM., W inkler, H., Van Gestel, J., Timmerman, P., Zhu M., Lee, E., Williams, P., de Chaffoy, D., Hui , M., Lee, E., Williams, P., de Chaffoy, D., Hui tric, E., Hoffner, S., Cambau, E., Truffot-Per not, C., Lounis, N. and Jarlier, V., “A diaryl quinoline drug active on the ATP synthas e of Mycobacterium tuberculosis”, Science (2005), 307: pp. 223 - 227). In the phase II clinical trial of drug-susceptible TB, after 7 days of treatment with 400 mg, BDQ was measured in sputum at Cmax 5 μg / ml, which was equivalent to the serum concentration observed in the same treatment regimen (Rustomje e, R., Diacon, A.H., Allen, J., Venter, A., Reddy , C., Patientia, R.F., Mthiyane, T.C.P., De Marez , T., van Heeswijk, R., Kerstens, R., Koul, A., De Beule, K., Donald, P.R. and McNeeley, D.F., “ Early Bactericidal Activity and Pharmaco kinetics of the Diarylquinoline TMC207 i n Treatment of Pulmonary Tuberculosis”, A ntimicrobial Agents and Chemotherapy(200 8), 52(8): pp. 2831 - 2835; Lounis, N., Gevers, T ., Van Den Berg, J. and Andries, K., “Impact of the Interaction of R207910 with Rifam pin on the Treatment of Tuberculosis Stu died in the Mouse Model”,Antimicrobial A gents and Chemotherapy(2008),52(10):pp.3 568-3572. This high tissue permeability, along with the extended tissue half-life, results in a long effective half-life of 24 hours and an extended terminal half-life of 5.5 months (Andries, K., Verhasselt, P., Guillemont, J., Goehlmann, HW H., Neefs, JM., Winkler, H., Van Gestel, J., Ti mmerman, P., Zhu, M., Lee, E., Williams, P., de Chaffoy, D., Huitric, E., Hoffner, S., Cambau, E., Truffot-Pernot, C., Lounis, N. and Jarlie r, V., “A diarylquinoline drug active on t he ATP synthase of Mycobacterium tubercu losis”, Science(2005),307:pp.223-227; Jans sen Pharmaceutical Companies, Briefing Do cument “TMC207(bedaquiline)Treatment of P atient with MDR-TB”, FDA Anti-Infective D rugs Advisory Committee Meeting(November 28,2012)pp.1-253). 28,2012)pp.1-253).

[0015] Despite the benefits of adding BDQ to the mycobacterial treatment plan, adverse events related to treatment Elephants are recognized. The most common affected tissues include the liver and heart tissues, and for the latter, the most common is associated with QT interval prolongation and electrical rhythm disorders (Kwon, YS. And Koh, WJ., “Synthetic investigational new drugs for the treatment of tuberculosis”, Exper t Opinion on Investigational Drugs (2016) , 25(2): pp.183 - 193; Goulooze, SC., Cohen, AF. and Rissmann, R., “Bedaquiline“, British Jo urnal of Clinical Pharmacology (2015), 80( 2): pp.182 - 184; Kakkar, AK. and Dahiya, N., “B edaquiline for the treatment of resistan t tuberculosis: promises and pitfalls.”, T uberculosis (2014), 94(4): pp.357 - 362). Importantly, an increased mortality is also associated with the current BDQ therapy, but the deaths are due to respiratory disorders and not due to the toxicity of BDQ (Diacon, AH., Pym, A., Grobusch, MP., de los Rios, JM.., Gotuzzo, E., Vasilyeva, I. , Leimane, V., Andries, K., Bakare, N., De Mare z, T., Haxaire - Theeuwes, M., Lounis, N., Meyvi sch, P., De Paepe, E. and van Heeswijk, RPG., “Multidrug-Resistant Tuberculosis and Cu lture Conversion with Bedaquiline”,The N ew England Journal of Medicine(2014),317 :pp.723-732;Mingote,LR.,Namutamba,D.,Api na,F.,Barnabas,N.,Contreras,C.,Elnour,T. ,Frick,MW.,Lee,C.,Seaworth,B.,Shelly,D., Skipper,N.and dos Santos Filho,ET.,“The use of bedaquiline in regimens to treat drug-resistant and drug-susceptible tube rculosis:a perspective from tuberculosis -affected communities”,Lancet(2015),385: pp.477-479).

[0016] Along with further concerns regarding the drug-drug interactions of BDQ, particularly those between BDQ and anti-TB drugs and antiviral drugs for the treatment of human immunodeficiency virus (HIV) (which has a high co-infection rate with TB), concerns have arisen regarding the interaction between them (http: / / apps.who.int / iris / bitstream / 10665 / 191102 / 1;987924156650 9eng.pdf) (last accessed on January 4, 2018)). Indeed, co-treatment of BDQ with rifamycin group antibiotics induces the CYP enzyme activity of rifampicin ​due to the ability, the BDQ AUC has been shown to decrease by up to 59% (van Heeswijk, RPG., Dannemann, B. and Hoetelmans , RMW., “Bedaquiline: a review of human pha rmacokinetics and drug-drug interactions ”, Journal of Antimicrobial Chemotherapy( 2014), 69: pp.2310-2318). Similar to a very large number of antiviral drugs, the co-administration of BDQ and lopinavir / ritonavir results in a decrease in antiviral concentration instead of an increase in BDQ concentration due to the interaction. However, many of these tests are single-dose interactions, and it should be noted that due to the long residence time of BDQ, longer treatment tests are required. Instead of causing an increase in BDQ concentration, the co-administration of BDQ and lopinavir / ritonavir results in a decrease in antiviral concentration due to the interaction. However, many of these tests are single-dose interactions, and it should be noted that due to the long residence time of BDQ, longer treatment tests are required. However, many of these tests are single-dose interactions, and it should be noted that due to the long residence time of BDQ, longer treatment tests are required. However, many of these tests are single-dose interactions, and it should be noted that due to the long residence time of BDQ, longer treatment tests are required. should be noted.

[0017] Regarding the advantages of pulmonary delivery of antimycobacterial therapy, it has been outlined by Das (Das, S., Tuck er, I., and Stewart, P., “Inhaled Dry Powder Combinations for Treating Tuberculosis” , Current Drug Delivery(2015), 12: pp.26-39 ), and is as follows, for example.

[0018] First, the concentration of the drug in the lungs is higher compared to intramuscular administration. This higher drug concentration helps to prevent biofilm formation and reduces the risk of drug resistance. This higher drug concentration helps to prevent biofilm formation and reduces the risk of drug resistance.

[0019] The frequency of administration can be reduced because the drug remains in the lungs for a longer period of time compared to intramuscular and intravenous administration. This is because the drug remains in the lungs for a longer period of time compared to intramuscular and intravenous administration.

[0020] Reduced doses of drugs are required for pulmonary delivery compared to oral administration. Reduced toxicity is due to: Associated with reduced amounts of drug in the body.

[0021] Improved patient compliance is anticipated due to reduced dose, frequency and duration of treatment. do.

[0022] Uptake of drug microparticles by alveolar macrophages reverses "alternative activation" It can induce a bactericidal response.

[0023] Pulmonary delivery is suitable for delivery of drugs when optimal drug concentrations at the site of action are difficult to achieve.

[0024] Pulmonary delivery offers advantages for drugs that are poorly water soluble and difficult to formulate for injection. .

[0025] The pulmonary route avoids injections in the case of injectable drugs that require frequent administration over a long period of time. This is advantageous in that

[0026] Degradation of drugs by the gastrointestinal environment can be avoided by pulmonary administration. Rifampicin, which is degradable in the presence of the acidic environment of the stomach, is administered via the pulmonary route. obtain.

[0027] Finally, and of that relevance, pulmonary administration allows for the avoidance of hepatic first-pass metabolism.

[0028] Many of these potential advantages are due to the pulmonary administration of bedaquiline as opposed to the oral administration of bedaquiline. This can be achieved by, for example, bedaquiline, which has low water solubility. During oral treatment (400 mg once daily for 2 weeks, followed by 200 mg three times a week for 22 weeks), After ingestion of the agent, it is necessary to first dissolve bedaquiline in gastric juice and then diffuse it into the blood. Due to its high penetration rate into the spleen and binding to plasma proteins in serum, the amount of drug available to enter the lungs is reduced. After circulation to the lungs, the drug needs to diffuse into the lung tissue and then into the macrophages where mycobacteria are present. Since the solubility of bedaquiline is extremely low, this is a very inefficient system and much of the bedaquiline is excreted with the feces. By delivering bedaquiline directly to the lung periphery, it can be directly taken up by macrophages and act against mycobacteria. Bypassing the inefficient oral delivery route means that the lung dose can be lower than the oral dose (10 mg - 100 mg, depending on the characteristics of inhalation administration). Bedaquiline has a very long half-life of over 5 months in tissues. The treatment period can be reduced compared to oral therapy by directly depositing bedaquiline into the lung tissue. Therefore, the use of aerosolized administration of bedaquiline in patients with multi-drug resistant tuberculosis or extensively drug-resistant tuberculosis infections needs to further improve the treatment outcome of the patients and may shorten the duration of the current treatment plan. The group of nontuberculosis mycobacteria (NTM), previously referred to as atypical or widely distributed mycobacteria, contains over 150 species. NTM are found naturally widely and can show a wide variety of diversity. They are present in soil, ground, and drinking water, as well as pasteurized milk or

[0029] Bedaquiline has a very long half-life of over 5 months in tissues. The treatment period can be reduced compared to oral therapy by directly depositing bedaquiline into the lung tissue. Therefore, the use of aerosolized administration of bedaquiline in patients with multi-drug resistant tuberculosis or extensively drug-resistant tuberculosis infections needs to further improve the treatment outcome of the patients and may shorten the duration of the current treatment plan.

[0030] Therefore, the use of aerosolized administration of bedaquiline in patients with multi-drug resistant tuberculosis or extensively drug-resistant tuberculosis infections needs to further improve the treatment outcome of the patients and may shorten the duration of the current treatment plan. The use of aerosolized administration of bedaquiline in patients with multi-drug resistant tuberculosis or extensively drug-resistant tuberculosis infections needs to further improve the treatment outcome of the patients and may shorten the duration of the current treatment plan. The use of aerosolized administration of bedaquiline in patients with multi-drug resistant tuberculosis or extensively drug-resistant tuberculosis infections needs to further improve the treatment outcome of the patients and may shorten the duration of the current treatment plan.

[0031] Previously referred to as atypical or widely distributed mycobacteria, the group of nontuberculosis mycobacteria (NTM) contains over 150 species. The group of nontuberculosis mycobacteria (NTM), previously referred to as atypical or widely distributed mycobacteria, contains over 150 species. NTM includes over 150 species. NTM are found naturally widely and can show a wide variety of diversity. They are found naturally widely and can show a wide variety of diversity. They are present in soil, ground, and drinking water, as well as pasteurized milk or can be detected in foods such as cheese. Generally, NTM are considered to have low pathogenicity. Nevertheless, they can cause serious diseases in humans, especially in immunocompromised individuals or those suffering from pre-existing lung diseases. Currently, NTM are classified according to their growth rate and are divided into slow-growing (SGM) and rapid-growing (RGM) mycobacteria. eria).

[0032] The slow-growing Mycobacterium avium complex (MAC) is among the most important and frequent pathogenic NTM, including the Mycobacterium avium species, Mycobacterium chimaera species, and Mycobacterium intracellulare species. Mycobacterium kansasii, Mycobacterium malmoense, Mycobacterium xenopi, Mycobacterium simiae, Mycobacterium abscessus, Mycobacterium gordonae, Mycobacterium fortuitum, se), m), and Mycobacterium chelonae ae), like them, often cause lung infections. Mycobacterium marinum ) is involved in skin and soft tissue infections such as aquarium granuloma.

[0033] In particular, RGM causes severe life-threatening chronic lung diseases and is also involved in disseminated, often fatal infections. Infections typically result from contaminants and invasive procedures, including catheters, non-sterile surgical procedures or injections, and the implantation of foreign bodies. Exposure to showerheads and Jacuzzis has also been reported as a risk for infection. NTM typically causes opportunistic infections in patients with chronic lung diseases such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), etc., and other immunocompromised patients.

[0034] In recent years, rapidly growing mycobacterium abscessus (RGM) strains, including Mycobacterium abscessus subsp. abscessus (M.a.ab scessus), Mycobacterium abscessus bolletii., and Mycobacterium abscessus massiliense, have become important The Mycobacterium abscessus group strains (Mycobacterium abscessus complex, MABSC) ​​​​has emerged as a human pathogen and is associated with significantly higher mortality rates than any other RGM .

[0035] Mycobacterium abscessus infection in CF patients causes the expansion of lung destruction and is particularly problematic because it is often untreatable with a high failure rate of 60 - 66% (see, for example, Obregon-Henao A et al, Antimicrobial Agents and Chemotherapy, November 2015, Vol59, No11, p.6904 -6912; Qvist, T., Pressler, T., Hoiby, N. and K atzenstein, TL., “Shifting paradigms of nontuberculous mycobacteria in cystic fibrosis”, Respiratory Research(2014), 15(1): p p.41 - 47).

[0036] Human infections with NTM have become more closely associated with the emergence of the human acquired immunodeficiency syndrome (AIDS) pandemic. Mycobacteria from the Mycobacterium avium complex (MAC) have been identified as a major cause of opportunistic infections in patients infected with the human immunodeficiency virus (HIV).

[0037] Some species of NTM are known to form biofilms. Biofilms are embedded within an extracellular matrix that provides stability and resistance to the human immune system .​​​​​​​​​​ They are microcolonies of the bacteria that have been formed. In recent years, some species of NTM have been shown to form biofilms that enhance resistance to disinfectants and antibacterial agents. Biofilm assembly proceeds through several phases, including reversible attachment, irreversible attachment, bacterial aggregation, organization, and biofilm formation via signal transduction, and finally dispersion. During this process, bacteria express a matrix containing extracellular polymeric substances (EPS), such as polysaccharides, lipids, and nucleic acids, in order to form a complex three-dimensional structure (see, for example, Sousa S.et al.,International Journal of Mycobacteriology 4(2015),36-43). Specifically, mycobacterial EPS is essentially different from other biofilms because mycobacteria do not produce extracellular polysaccharides (see, for example, Zambr ano MM,Kolter R.Mycobacterial biofilms:a greasy way to hold it together.Cell.200 5). Mycobacterial biofilms vary among species but may contain mycolic acids, glycopeptidolipids, mycolyl-diacylglycerol, lipooligosaccharides, lipopeptides, and extracellular DNA (for an overview and original research, see Rose SJ,Babrak LM,Be rmudez LE(2015)Mycobacterium avium Posse sses Extracellular DNA that Contributes to Biofilm Formation,Structural Integrit y,and Antibiotic Resistance.PLoS ONE 10(8): e0135715.doi:10.1371 / journal.pone.0135715). y,and Antibiotic Resistance.PLoS ONE 10(8): e0135715.doi:10.1371 / journal.pone.0135715). to Biofilm Formation,Structural Integrity, y, and Tolerance to Antibiotics, in PLoS ONE (derived from). Assembly within biofilms is known to enhance resistance to antibacterial agents (see, for example, Faria S. et al., Journal of Pathogens, Vol 2015, Article ID 809014). As a novel approach in the treatment of NTM lung infections, the delivery of aerosolized liposomal amikacin / inhaled amikacin solution by jet nebulizer (Rose S. et al., 2014, PLoS ONE, Volume 9, Issue 9, e10870 3, and Olivier K. et al, Ann Am Thorac Soc Vol

[0038] 11, No1, pp.30 - 35), as well as the inhalation of dry powder microparticles of anti - TB drugs for lung delivery (Cholo M et al., J Antimicrob Chemother. 2012 Feb;67(2):290 - 8 and Fourie B. and Nette y O., 2015 Inhalation Magazine, Verma 2013 3, and Olivier K. et al, Ann Am Thorac Soc Vol 11, No1, pp.30 - 35), as well as the inhalation of dry powder microparticles of anti - TB drugs for lung delivery (Cholo M et al., J Antimicrob Chemother. 2012 Feb;67(2):290 - 8 and Fourie B. and Nette y O., 2015 Inhalation Magazine, Verma 2013 Antimicrob Agents Chemother) have been proposed.

Summary of the Invention

Problems to be Solved by the Invention

Problems to be Solved by the Invention

[0039] Inhaled amikacin after initial treatment with parenteral aminoglycosides, tigecycline, along with other promising oral antibiotics such as linezolid, delamanid, and bedaquiline, and multiple combination regimens involving surgical procedures in selected cases, are for the treatment of NTM lung disease

Problems to be Solved by the Invention

[0040] A combination of bedaquiline and clofazimine used against Mycobacterium tuberculosis has shown synergy (see, for example, Cokol, M. et al., “Efficient Measurement an d factorization of high-order drug inter actions in Mycobacterium tuberculosis”, S ciences Advances 2017:3:e170881, 11 Octob er 2017).

[0041] Bedaquiline has also been shown to have an additive effect with amikacin (see, for example, htt ps: / / www.escmid.org / escmid_pulications / e scmid_elibrary / material / ?mid=42441).

[0042] The low solubility of bedaquiline in water results in low oral bioavailability and high microbial resistance, and to solubilize and stabilize the drug for formulations in a liquid aqueous carrier, for example, spray Specific techniques are required to obtain deposition of aerosol particles in the lower lungs by aerosolization with a nebulizer. Further required.

Means for Solving the Problem

[0043] The present invention provides bedaquiline in the form of a suspension adapted to a suitable nebulizer or as a dry powder adapted to a dry powder inhaler, thereby also achieving significantly enhanced delivery of aerosolized bedaquiline to the lower lungs (i.e., the trachea, bronchioles, and alveoli of the central and lower peripheral lungs). The present invention provides an aerosol having aerosol particles of a size that facilitates delivery to the alveoli and bronchioles, thereby providing an aerosol that substantially enhances the therapeutic effect. The aerodynamic particle size suitable for targeting the alveoli and bronchioles is between 1 and 5 μm. Larger aerosol particles are selectively deposited in the upper lungs, i.e., the bronchi and trachea, and the mouth and pharynx, i.e., the oropharyngeal region. Therefore, the inhalation device is adapted to generate an aerosol having a mass median aerodynamic diameter (MMAD) in the range of about 1 to about 5 μm, preferably in the range of about 1 to about 3 μm. In a further embodiment, the particle size distribution is narrow and has a geometric standard deviation (GSD) of less than about 2.5. This results in the generation of aerosol particles suitable for significantly enhanced delivery of aerosolized bedaquiline. Thereby, aerosol particles suitable for significantly enhanced delivery of aerosolized bedaquiline to the lower lungs (i.e., the trachea, bronchioles, and alveoli of the central and lower peripheral lungs) are generated.

[0044] The present invention provides an aerosol having aerosol particles of a size that facilitates delivery to the alveoli and bronchioles, thereby providing an aerosol that substantially enhances the therapeutic effect. The aerodynamic particle size suitable for targeting the alveoli and bronchioles is between 1 and 5 μm. Larger aerosol particles are selectively deposited in the upper lungs, i.e., the bronchi and trachea, and the mouth and pharynx, i.e., the oropharyngeal region. Therefore, the inhalation device is adapted to generate an aerosol having a mass median aerodynamic diameter (MMAD) in the range of about 1 to about 5 μm, preferably in the range of about 1 to about 3 μm. In a further embodiment, the particle size distribution is narrow and has a geometric standard deviation (GSD) of less than about 2.5. Thereby, aerosol particles suitable for significantly enhanced delivery of aerosolized bedaquiline to the lower lungs (i.e., the trachea, bronchioles, and alveoli of the central and lower peripheral lungs) are generated. Larger aerosol particles are selectively deposited in the upper lungs, i.e., the bronchi and trachea, and the mouth and pharynx, i.e., the oropharyngeal region. Therefore, the inhalation device is adapted to generate an aerosol having a mass median aerodynamic diameter (MMAD) in the range of about 1 to about 5 μm, preferably in the range of about 1 to about 3 μm. In a further embodiment, the particle size distribution is narrow and has a geometric standard deviation (GSD) of less than about 2.5. In a further embodiment, the particle size distribution is narrow and has a geometric standard deviation (GSD) of less than about 2.5. Thereby, aerosol particles suitable for significantly enhanced delivery of aerosolized bedaquiline to the lower lungs (i.e., the trachea, bronchioles, and alveoli of the central and lower peripheral lungs) are generated.

[0045] The aerosol dose, formulation, and delivery system are described, for example, in Gonda, I. “Aerosols for delivery of therapeutic and diagnost ic agents to the respiratory tract”, Crit ical Reviews in Therapeutic Drug Carrier Systems, 6, 273 - 314 (1990), and Moren, "Aeroso l dosage forms and formulations", Aerosol s in Medicine, Principles, Diagnosis and T herapy, Moren, et al., Eds. Elsevier, Amsterd am, 1985, may be selected according to specific therapeutic uses as described therein.

Mode for Carrying Out the Invention

[0046] The present invention is based on the discovery that by transpulmonary administration of bedaquiline in the form of an aerosol, deposition of the active agent in the lower ( i.e., deeper) lungs can be achieved, thereby significantly enhancing the bioavailability of this extremely hydrophobic BCS class II agent and obtaining a significantly enhanced therapeutic effect associated with reduced systemic side effects.

[0047] In another aspect, this finding presents improved antibiotic therapy in infections caused by mycobacteria and Gram - positive bacteria, particularly pulmonary infections caused by NTM, CF, COPD, and opportunistic infections in immunocompromised patients, such as opportunistic infections in HIV patients.

[0048] Furthermore, the present invention aims to overcome the systemic side effects of established oral treatment regimens for pulmonary infections caused by Gram - positive bacteria, particularly pulmonary TB and NTM infections, and to reduce the dosage and duration of treatment with bedaquiline.

[0049] It is understood by those skilled in the art that any combination of each of the individual features disclosed herein in the present application is also disclosed.

[0050] definition The term "pharmaceutically acceptable salt" refers to a compound that retains the biological effectiveness and properties of the compounds of the present invention. This refers to salts which are not biologically or otherwise undesirable. In this case, the compounds of the present invention contain amino and / or carboxyl groups or groups similar thereto. Due to the presence of , acid and / or base salts can be formed. Pharmaceutically acceptable acid addition salts are Salts may be formed with inorganic and organic acids. Inorganic acids from which salts may be derived include, for example, salts of Acids from which salts can be derived include hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. For example, acetic acid, propionic acid, naphthoic acid, oleic acid, acid, palmitic acid, pamoic (embonic) acid, stearic acid, glycolic acid, pyruvic acid , oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, ascorbyl phosphate Vic acid, glucoheptonic acid, glucuronic acid, lactic acid, lactobionic acid, tartaric acid, benzoic acid, Cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid , salicylic acid, etc.

[0051] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Possible inorganic bases include, for example, sodium, potassium, lithium, ammonium , calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc; Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. The organic bases from which the salts can be derived include, for example, primary, secondary, and tertiary Primary amines, substituted amines, e.g., naturally occurring substituted amines, cyclic amines, basic ions Specific examples include ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, histidine, arginine, lysine, benethamine , N-methyl-glucamine, and ethanolamine. Other acids include dodecyl sulfuric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, and saccharin.

[0052] According to the present invention, unlike the free base, the use of the fumarate, sulfate, tartrate, chloride, or phosphate of bedaquiline, particularly the fumarate of bedaquiline, is preferred.

[0053] As used herein, the term "pharmaceutically acceptable derivative" of a compound is, for example, a prodrug of the aforementioned compound. Generally, a prodrug is a derivative of a compound that has the ability to generate the active form of the compound upon administration. Such derivatives may be, for example, esters or amides of carboxyl groups, carboxyl esters of hydroxyl groups, or phosphate esters of hydroxyl groups.

[0054] "Patient" means a mammal, preferably a human, in need of prevention and / or treatment as described herein.

[0055] "Therapeutically effective amount", "therapeutically effective dose", or "medically effective amount" means the amount of bedaquiline as disclosed in the present invention that has a therapeutic effect in a patient. The dose of bedaquiline that is useful in treatment is a therapeutically effective amount. Thus, as used herein, a therapeutically effective amount is determined by clinical trial results refers to the amount of bedaquiline that produces the desired therapeutic effect.

[0056] The amount and daily dose of bedaquiline can be routinely determined by those skilled in the art and will vary depending on several factors , for example, depending on the particular microbial strain involved. This amount may further depend on the patient's height, weight, gender, age and medical history. In the case of prophylactic treatment, the therapeutically effective amount is the amount effective to prevent microbial infection.

[0057] "Therapeutic effect" includes reducing to some extent one or more of the symptoms of the infection and curing the infection. "Cure" means the removal of the symptoms of active infection, for example, the overall or substantial reduction of the excess members of the viable microorganisms involved in the infection to a point at or below the detection threshold by traditional measurements. However, certain long-term or permanent effects of the infection may persist even after cure (such as extensive tissue damage, etc.). As used herein when, "therapeutic effect" is defined as a statistically significant decrease in the bacterial load in the host, the emergence of resistance, or an improvement in the symptoms of the infection when measured by human clinical outcomes or animal tests. However, certain long-term or permanent effects of the infection may persist even after cure (such as extensive tissue damage, etc.). As used herein when, "therapeutic effect" is defined as a statistically significant decrease in the bacterial load in the host, the emergence of resistance, or an improvement in the symptoms of the infection when measured by human clinical outcomes or animal tests. "Treat", "treatment", or "treating", as used herein when, refers to administering a pharmaceutical composition / formulation to a patient for the purpose of prevention and / or treatment.

[0058] The terms "prophylactic treatment" or "prevention" refer to treating patients who are not yet infected but are susceptible to or at risk of a particular infection. The term "therapeutic treatment" as used herein refers to administering a pharmaceutical composition / formulation to a patient for the purpose of prevention and / or treatment.

[0059] The term "prophylactic treatment" or "prevention" refers to treating patients who are not yet infected but are susceptible to or at risk of a particular infection. The term "therapeutic treatment" refers to treating patients who are already infected with a particular infection. Refers to treating patients who are already suffering from an infection. Thus, in a preferred embodiment, the treatment is administration of a therapeutically effective amount of bedaquiline to a mammal (for either treatment or prevention purposes).

[0060] Unless otherwise specified herein, the term "inhalation" means oral inhalation into the lungs .

[0061] Unless otherwise specified herein, the term "infection" when used herein means pulmonary infection .

[0062] Unless otherwise specified, the term "substantially" when used to refer to the purity of a compound indicates that the purity of the compound is 95% or greater.

[0063] Unless otherwise specified, the term "suitable particle size" refers to the particle size of bedaquiline provided by a pharmaceutical combination that, in a composition or when administered to a patient , provides the desired therapeutic effect. .

[0064] Unless otherwise specified, the term "suitable concentration" refers to the concentration of a component in a composition or pharmaceutical combination that provides a pharmaceutically acceptable composition or combination .

[0065] Pharmaceutical Compositions and Combinations The following water grades are particularly applicable to the present invention: sterile purified water, sterile water for injection, sterile water for washing , sterile water for inhalation (USP) and corresponding water grades according to, for example, the European Pharmacopoeia or the National Formulary. .

[0066] An aqueous electrolyte solution as used in accordance with the present invention as an aqueous liquid carrier contains sodium chloride, potassium chloride, lithium chloride, magnesium chloride, calcium chloride or a mixture thereof. It may further contain sodium chloride, potassium chloride, lithium chloride, magnesium chloride, calcium chloride or a mixture thereof.

[0067] The aqueous liquid carrier is preferably an isotonic saline solution (about 150 mM NaCl, preferably 0.9% NaCl corresponding to 154 mM NaCl).

[0068] Thus, in one embodiment of the present invention, there is provided a pharmaceutical composition comprising: (a) a therapeutically effective amount of bedaquiline or a pharmaceutically acceptable derivative or salt thereof; (b) a nonionic surfactant having a hydrophilic-lipophilic balance value greater than 10; and (c) an aqueous liquid carrier selected from water, isotonic saline, buffered saline and aqueous electrolyte solution, wherein bedaquiline or a pharmaceutically acceptable derivative or salt thereof is provided in the form of particles in a suspension, and the bedaquiline particles or particles of a pharmaceutically acceptable salt of bedaquiline have a median size of less than 5 μm and a D90 of less than 6.5 μm. In another embodiment, the bedaquiline particles, or a pharmaceutically acceptable salt thereof, have a median size of less than 2 μm and a D90 of less than 3 μm. It may further contain a nonionic surfactant having a hydrophilic-lipophilic balance value greater than 10. And (c) an aqueous liquid carrier selected from water, isotonic saline, buffered saline and aqueous electrolyte solution. Wherein bedaquiline or a pharmaceutically acceptable derivative or salt thereof is provided in the form of particles in a suspension, and the bedaquiline particles or particles of a pharmaceutically acceptable salt of bedaquiline have a median size of less than 5 μm and a D90 of less than 6.5 μm. And the bedaquiline particles or particles of a pharmaceutically acceptable salt of bedaquiline are provided in the form of particles in a suspension. And the bedaquiline particles or particles of a pharmaceutically acceptable salt of bedaquiline have a median size of less than 5 μm and a D90 of less than 6.5 μm. A pharmaceutical composition is provided. In another embodiment, the bedaquiline particles, or a pharmaceutically acceptable salt thereof, have a median size of less than 2 μm and a D90 of less than 3 μm. Or a pharmaceutically acceptable salt thereof has a median size of less than 2 μm and a D90 of less than 3 μm.

[0069] In a further embodiment of the present invention, there is provided a pharmaceutical composition comprising: (a) a therapeutically effective amount of bedaquiline; (b) a nonionic surfactant having a hydrophilic-lipophilic balance value greater than 10; and (c) an aqueous liquid carrier selected from water, isotonic saline, buffered saline and aqueous electrolyte solution, wherein bedaquiline is provided in the form of particles in a suspension, and the bedaquiline particles have a median size of less than 5 μm and a D90 of less than 6.5 μm. It may further contain a nonionic surfactant having a hydrophilic-lipophilic balance value greater than 10. And (c) an aqueous liquid carrier selected from water, isotonic saline, buffered saline and aqueous electrolyte solution. Wherein bedaquiline is provided in the form of particles in a suspension, and the bedaquiline particles have a median size of less than 5 μm and a D90 of less than 6.5 μm. A pharmaceutical composition is provided.​​​ In a further embodiment, the vedacillin particles have a median size of less than 2 μm and a D90 of less than 3 μm.

[0070] In another embodiment of the present invention, in the pharmaceutical composition according to any of the above embodiments, the non-ionic surfactant is polysorbate 20 (e.g., Tween (registered trademark) 20, polysorbate 60 (e.g., Tween (registered trademark) 60), polysorbate 80 (e.g., Tween ( registered trademark) 80), stearyl alcohol, polyethylene glycol derivative of hydrogenated castor oil having a hydrophilic-lipophilic balance value of 14-16 (e.g., Cremophor (registered trademark) RH40), polyethylene glycol derivative of hydrogenated castor oil having a hydrophilic-lipophilic balance value of 15-17 (e.g., Cremophor (registered trademark) RH60), sorbitan monolaurate (e.g., Span (registered trademark) 20), sorbitan monopalmitate (e.g., Span ( registered trademark) 40), sorbitan monostearate (e.g., Span (registered trademark) 60), poly oxyethylene (20) oleyl ether (e.g., Brij (registered trademark) 020), poly oxyethylene (20) cetyl ether (e.g., Brij (registered trademark) 58), polyoxy ethylene (10) cetyl ether (e.g., Brij (registered trademark) C10), polyoxy ethylene (10) oleyl ether (e.g., Brij (registered trademark) O10), polyoxy ethylene (100) stearyl ether (e.g., Brij (registered trademark) S100), poly oxyethylene (10) stearyl ether (e.g., Brij (registered trademark) S10), polyoxyethylene (20) stearyl ether (e.g., Brij (registered trademark) S20) and polyoxyethylene (4) lauryl ether (e.g., Brij (registered trademark) L4), poly ​ Ceteth-20 (e.g., Brij® 93), poly oxythylene (2) cetyl ether (e.g., Brij® S2), caprylocapryl oyl polyoxyl-8 glyceride (e.g., Labrasol®), stearic acid poly ethylene glycol (20) (e.g., Myrj™ 49), stearic acid poly ethylene glycol (40) (e.g., Myrj™ S40), stearic acid poly ethylene glycol (100) (e.g., Myrj™ S100), stearic acid poly ethylene glycol (8) (e.g., Myrj™ S8), and stearic acid polyoxy l 40 (e.g., Myrj™ 52), and mixtures thereof.

[0071] In a preferred embodiment of the present invention, there is provided a pharmaceutical composition according to any of the above embodiments wherein the nonionic surfactant is polysorbate 80 and the aqueous liquid carrier is distilled water , hypertonic saline, or isotonic saline. Another preferred embodiment provides that the hypertonic saline is 1% to 7% (weight / volume) sodium chloride. Another preferred embodiment provides that the nonionic surfactant is ultra-high purity polysorbate 80 (e.g., polysorbate 80 (Hx2) of NOF Corporation), and the aqueous liquid carrier is isotonic saline.

[0072] In another embodiment of the present invention, in a pharmaceutical composition according to any of the above composition embodiments, the weight molar osmotic concentration of the composition is in the range of 200 to 700 mOsm / kg. Preferably in an embodiment, the weight molar osmotic concentration of the composition is in the range of 300 to 400 mOsm / kg range.

[0073] In a further embodiment of the present invention, there is provided a pharmaceutical composition according to any of the above embodiments, wherein the concentration of the nonionic surfactant ranges from 0.001% to 5% (v / v) of the total composition and the amount of bedaquiline ranges from 0.1% to 20% (w / v) of the total composition. A pharmaceutical composition is provided.

[0074] In a further embodiment of the present invention, (1) to obtain a suspension containing bedaquiline with an appropriate particle size, a step of homogenizing a suspension of bedaquiline, a nonionic surfactant, and water; and (2) a step of adjusting the pH of the suspension obtained from (1) to a pH between pH 5.5 and pH 7.5, a step of adjusting the sodium chloride concentration to an appropriate concentration; and (4) a step of adjusting the weight molar osmotic concentration to an appropriate level, A pharmaceutical composition according to any of the above composition embodiments prepared by a method comprising the steps. In a preferred embodiment, the pH is adjusted to 6.5 and the sodium chloride concentration is 154 mM sodium chloride. In another preferred embodiment, the homogenization in step (1) is carried out by high-pressure homogenization, high-shear homogenization, wet milling, ultrasonic homogenization, or a combination of such processes. In another preferred embodiment of the present invention, the homogenization of bedaquiline is carried out in a plurality of homogenization steps. In another embodiment of the present invention, (1) to obtain a suspension containing bedaquiline with an appropriate particle size, a step of homogenizing a suspension of bedaquiline and a non-aqueous liquid; (2) a step of isolating bedaquiline,

[0075] a step of adding bedaquiline to a nonionic surfactant and water; and (4) a step of adjusting the pH of the suspension obtained from (3) to a pH between pH 5.5 and pH 7.5, a step of isolating bedaquiline; (3) a step of adding bedaquiline to a nonionic surfactant and water; and (4) a step of adjusting the pH of the suspension obtained from (3) to a pH between pH 5.5 and pH 7.5, a step of adding bedaquiline to a nonionic surfactant and water; and (4) a step of adjusting the pH of the suspension obtained from (3) to a pH between pH 5.5 and pH 7.5, (4) a step of adjusting the pH of the suspension obtained from (3) to a pH between pH 5.5 and pH 7.5, A method comprising the steps of: (5) adjusting the sodium chloride concentration to an appropriate concentration There is provided a pharmaceutical composition according to any of the above composition embodiments, prepared by In a preferred embodiment, the pH is adjusted to 6.5 and the sodium chloride concentration is 154 mM of sodium chloride. In another preferred embodiment, the homogenization in step (1) is performed by high-pressure homogenization, high-shear homogenization, wet milling, ultrasonic homogenization, or a combination of such processes In another preferred embodiment of the present invention, the homogenization of bedaquiline is performed in a plurality of homogenization steps.

[0076] In another embodiment, (1) to obtain bedaquiline with an appropriate particle size, bedaquiline is micronized and (2) bedaquiline is added to a non-ionic surfactant and water, and (3) the pH of the suspension obtained from (2) is adjusted to a pH between pH 5.5 and pH 7.5 and (4) the sodium chloride concentration is adjusted to an appropriate concentration. There is provided a pharmaceutical composition according to any of the above composition embodiments, prepared by a method In a preferred embodiment, the pH is adjusted to 6.5 and the sodium chloride concentration is adjusted to 154 mM of sodium chloride. In another preferred embodiment, the micronization of bedaquiline is performed by jet milling, spray drying, ball milling, or supercritical fluid treatment In another preferred embodiment of the present invention, the micronization of bedaquiline is performed in a plurality of homogenization steps In a further embodiment, to obtain bedaquiline with an appropriate particle size, a non-ionic surfactant, containing an appropriate concentration of sodium chloride and adjusted to a pH between pH 5.5 and pH 7.5 is used.

[0077] In a further embodiment, to obtain bedaquiline with an appropriate particle size, a non-ionic surfactant, containing an appropriate concentration of sodium chloride and adjusted to a pH between pH 5.5 and pH 7.5 Prepared by a method comprising the step of homogenizing a suspension of bedaquiline in water There is provided a pharmaceutical composition according to any of the embodiments of the above composition. In a preferred embodiment the pH is adjusted to 6.5 and the sodium chloride concentration is adjusted to 154 mM sodium chloride In another preferred embodiment, the homogenization in step (1) is carried out by high-pressure homogenization , high-shear homogenization, wet grinding, ultrasonic homogenization, or a combination of such processes In another preferred embodiment of the present invention, the homogenization of bedaquiline is carried out in a plurality of homogenization steps

[0078] In another embodiment of the present invention, a composition adjusted by any of the embodiments of the above method wherein bedaquiline of appropriate particle size has an average size of less than 5 μm and a D 90 of less than 6.5 μm Particles are provided. In a preferred embodiment, bedaquiline of appropriate particle size

[0079] In another embodiment of the present invention, by an aerosolization of any of the embodiments of the composition with a nebulizer selected from an ultrasonic nebulizer, an electronic spray nebulizer, a vibrating membrane nebulizer, a jet nebulizer and a mechanical soft mist inhaler There is provided a pharmaceutical combination in the form of an inhalable aerosol, or any of the compositions prepared by any of the embodiments of the above method wherein the aerosol particles generated by the nebulizer have a mass median aerodynamic diameter of 1 to 5 μm. In another embodiment, the inhalable aerosol is targeted for deposition in the lower lungs. In a further embodiment, the nebulizer is 0.1 to 1.0 ml / ​​​Indicates the output speed per minute. In another embodiment, the total inhalation volume is between 1 ml and 5 ml. Another In an embodiment, the pharmaceutical combination is intended for use in the treatment and / or prevention of lung infections caused by mycobacteria or other Gram-positive bacteria. In a further embodiment, the infection is caused by mycobacterium species selected from nontubercul osis mycobacteria and Mycobacterium tuberculosis complex, and combinations thereof. In a further embodiment, the nontubercul osis mycobacteria are selected from Mycobacterium avium, Mycobacterium intracellu lare, Mycobacterium abscessus, and Mycobacterium leprae, and combinations thereof. In another embodiment, the infection is an opportunistic infection selected from MAC lung disease and nontuberculous infection in patients with cystic fibrosis, chronic obstructive pulmonary disease or acquired immunodeficiency syndrome. In another embodiment, the infection is a nontuberculous opportunistic mycobacterial infection in patients with cystic fibrosis. In a further embodiment, there is provided a pharmaceutical combination to be used as described above, where the pharmaceutical combination is clo fazimine or a pharmaceutically acceptable salt or derivative thereof, cefoxitin, amikacin , clarithromycin, pyrazinamide, rifampin, moxifloxacin, levofloxacin In another embodiment, the infection is an opportunistic infection selected from MAC lung disease and nontuberculous infection in patients with cystic fibrosis, chronic obstructive pulmonary disease or acquired immunodeficiency syndrome. In another embodiment, the infection is a nontuberculous opportunistic mycobacterial infection in patients with cystic fibrosis. In a further embodiment, there is provided a pharmaceutical combination to be used as described above, where the pharmaceutical combination is clo fazimine or a pharmaceutically acceptable salt or derivative thereof, cefoxitin, amikacin It is used to be administered before, simultaneously with, or after the administration of a drug selected from sasin, para - aminosalicylate, and mixtures thereof. In a further embodiment, the drug is clofazimine. In a further embodiment, the drug is amikacin.

[0080] In another embodiment of the present invention, any of the embodiments of the composition, or any of the compositions prepared by any of the embodiments of the above - mentioned method, is sprayed 4 - 7% hypertonic saline, metaperiodic acid, sodium dodecyl sulfate, sodium bicarbonate, tromethamine, silver nanoparticles, bismuth thiol, ethylenediaminetetraacetic acid, gentamicin - loaded phosphatidylcholine - modified gold nanoparticles, chelating agents, cis - 2 - decenoic acid, D - amino acids, D - enantiomer peptides, gallium mesoporphyrin IX, gallium protoporphyrin IX, curcumin, patulin, penicillic acid, baicalein, naringenin, ursolic acid, asiatic acid, corosolic acid, fatty acids, host - defense peptides, and antibacterial peptides, which are selected as agents for the dispersion and / or destruction of biofilms, mucolytics and / or mucoactive agents, and / or drugs for reducing biofilm formation. In another embodiment, the composition is administered before, simultaneously with, or after the administration of a drug selected from clofazimine or a pharmaceutically acceptable salt or derivative thereof, cefoxitin, amikacin, clarithromycin, pyrazinamide, rifampin, moxifloxacin, levofloxacin, and para - aminosalicylate, and mixtures thereof. In a further embodiment, the drug is clofazimine. In a further embodiment, the drug is amikacin.

[0081] In another embodiment, the sprayed 4-7% hypertonic saline, metaperiodic acid, sodium dodecyl sulfate, sodium bicarbonate, tromethamine, silver nanoparticles, bismuth thiol, ethylenedi aminetetraacetic acid, gentamicin-loaded phosphatidylcholine-modified gold nanoparticles, chelating agents, cis-2-decenoic acid, D-amino acids, D-enantiomeric peptides, gallium mesoporph hyrin IX, gallium protoporphyrin IX, curcumin, patulin, penicillic acid, baicalein, naringenin, ursolic acid, asiatic acid, corosolic acid, fatty acids, host defense peptides, and antibacterial peptides, for the dispersion and / or destruction of biofilms, mucolytics and / or mucotropic agents, and / or agents to reduce biofilm formation, are provided in a pharmaceutical combination to be used in combination. In a further embodiment, a pharmaceutical combination to be used as described above is provided, where the pharmaceutical combination is used before, simultaneously with, or after administration of a drug selected from clofazimine or a pharmaceutically acceptable salt or derivative thereof, cefoxitin, amikacin, clarithromycin, pyrazinamide, rifampin, moxifloxacin, levofloxacin, and para-aminosalicylic acid salts, and mixtures thereof. In a further embodiment, the drug is clofazimine. In a further embodiment, the drug is amikacin.

[0082] In another embodiment of the present invention, any pharmaceutical composition according to any of the embodiments of the composition, or any of the compositions prepared by any of the embodiments of the methods described above, is for the treatment of lung infections caused by mycobacteria or other Gram-positive bacteria and / or is provided for use in prophylaxis. In a further embodiment, the infection is caused by a mycobacterium species selected from nontuberculosis mycobacteria and the Mycobacterium tuberculosis complex, and combinations thereof. In another embodiment, the nontuberculosis mycobacteria are selected from Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium abscessus, and Mycobacterium leprae, and combinations thereof. In a further embodiment, the infection is an opportunistic infection selected from MAC lung disease and nontuberculosis infection in a patient having cystic fibrosis, chronic obstructive pulmonary disease or acquired immunodeficiency syndrome. In another embodiment, the infection is a nontuberculosis opportunistic mycobacteria infection in a patient having cystic fibrosis. In a further embodiment, the pharmaceutical composition for which the above use is intended is administered before, simultaneously with, or after administration of a drug selected from clofazimine or a pharmaceutically acceptable salt or derivative thereof, cefoxitin, amikacin, clarithromycin, pyrazinamide, rifampin, moxifloxacin, levofloxacin, and para-aminosalicylic acid salts, and mixtures thereof. In a further embodiment, the drug is clofazimine. In a further embodiment, the drug is amikacin. ​​​​​​​​​​​​

[0083] In a further embodiment of the present invention, when treating or providing prophylaxis against pulmonary infections caused by mycobacteria or other Gram-positive bacteria, a system is contemplated for use in the presentation of antibiotic activity, the system comprising: 1) (a) a therapeutically effective amount of bedaquiline ; (b) a nonionic surfactant having a hydrophilic-lipophilic balance value greater than 10; and (c ) an aqueous liquid carrier selected from water, isotonic saline, buffered saline and aqueous electrolyte solutions, a spray pharmaceutical formulation, and 2) a nebulizer, wherein the bedaquiline is present in the form of a suspension and the aerosol particles produced by the system have a mass median aerodynamic diameter of 1-5 μm . The system is provided.

[0084] In a further embodiment, a method of treating or preventing a pulmonary infection caused by mycobacteria or other Gram-positive bacteria in a patient in need thereof, the method comprising administering by inhalation a composition according to any of the embodiments of the composition described above. In a further embodiment, the infection is caused by mycobacterium species selected from nontuberculosis mycobacteria and Mycobacterium tuberculosis complex, and combinations thereof. In another embodiment , the nontuberculosis mycobacterium is Mycobacterium avium , Mycobacterium intracellulare . In another embodiment , the nontuberculosis mycobacterium is Mycobacterium avium , Mycobacterium intracellulare intracellulare, Mycobacterium abscessus terium abscessus, and Mycobacterium leprae In a further embodiment, the infection is selected from: MA in patients with cystic fibrosis, chronic obstructive pulmonary disease, or acquired immune deficiency syndrome In a further embodiment, the opportunistic infection is selected from tuberculosis, pulmonary disease, and nontuberculous infections. Mycobacterium tuberculosis is a nontuberculous opportunistic mycobacterial infection in patients with cystic fibrosis. In a further embodiment, the composition for inhalation comprises clofazimine or a pharma- ceutically acceptable salt thereof. or derivatives, cefoxitin, amikacin, clarithromycin, pyrazinamide, Fampin, moxifloxacin, levofloxacin, and para-aminosalicylate, and and mixtures thereof. In further embodiments, the drug is clofazimine or amikacin. In this case, the drug is clofazimine.

[0085] In another embodiment of the present invention, a method for preparing a pharmaceutical composition as described herein (1) suspending bedaquiline in order to obtain a suspension containing bedaquiline of suitable particle size; (2) homogenizing the suspension obtained from (1), the non-ionic surfactant and the water; (3) adjusting the pH of the solution to a pH between 5.5 and 7.5; and (4) adjusting the osmolality to an appropriate level. and adjusting the pH to 6.5. and the sodium chloride concentration is adjusted to 154 mM sodium chloride. In an embodiment, homogenization is carried out by high-pressure homogenization, wet grinding, ultrasonic homogenization, or a combination of such processes. In a further embodiment, homogenization is carried out in a plurality of homogenization steps. In a further embodiment, bedaquiline of appropriate particle size is particles having an average size of less than 5 μm and a D90 of less than 6.5 μm. In a further embodiment, bedaquiline of appropriate particle size is particles having an average size of less than 2 μm and a D90 of less than 3 μm. .

[0086] In another embodiment of the present invention, a method for preparing a pharmaceutical composition as described herein, comprising: (1) homogenizing a suspension of bedaquiline and a non-aqueous liquid to obtain a suspension of bedaquiline of appropriate particle size; (2) isolating bedaquiline; (3) adding bedaquiline to a non-ionic surfactant and water; (4) adjusting the pH of the suspension obtained from (3) to a pH between 5.5 and 7.5; and (5) adjusting the sodium chloride concentration to an appropriate concentration. In a further embodiment, the pH is adjusted to 6.5 and the sodium chloride concentration is adjusted to 154 mM sodium chloride. In a further embodiment, homogenization is carried out by high-pressure homogenization, wet grinding, ultrasonic homogenization, or a combination of such processes. In a further embodiment, homogenization is carried out in a plurality of homogenization steps. In a further embodiment, bedaquiline of appropriate particle size is particles having an average size of less than 5 μm and a D90 of less than 6.5 μm. In a further embodiment, bedaquiline of appropriate particle size is particles having an average size of less than 2 μm and a D90 of less than 3 μm.

[0087] ​​​​​​​​​​​​​​​​ In another embodiment of the present invention, a method for preparing a pharmaceutical composition as described herein comprising: (1) a step of micronizing bedaquiline to obtain bedaquiline with an appropriate particle size , (2) a step of adding bedaquiline to a nonionic surfactant and water, and (3) a step of adjusting the pH of the suspension obtained from ( 2) to a pH between pH 5.5 and pH 7.5 , and (4) a step of adjusting the sodium chloride concentration to an appropriate concentration, is provided . In a further embodiment, the pH is adjusted to 6.5 and the sodium chloride concentration is adjusted to 154 m M sodium chloride. In a further embodiment, the micronization of bedaquiline is carried out by jet milling, spray drying, ball milling, or supercritical fluid treatment . In a further embodiment, the micronization of bedaquiline is carried out in a plurality of micronization steps . In a further embodiment, bedaquiline with an appropriate particle size is particles having an average size of less than 5 μm and a D90 of less than 6.5 μm. In a further embodiment, bedaquiline with an appropriate particle size is particles having an average size of less than 2 μm and a D90 of less than 3 μm . .

[0088] In another embodiment of the present invention, a method for preparing a pharmaceutical composition as described herein comprising a step of homogenizing a suspension of bedaquiline in water containing a nonionic surfactant, an appropriate concentration of sodium chloride, and adjusted to a pH between pH 5.5 and pH 7.5 to obtain bedaquiline with an appropriate particle size is provided . In a further embodiment, the pH is adjusted to 6.5 and the sodium chloride concentration is adjusted to 154 mM sodium chloride . In a further embodiment, the homogenization is carried out by high-pressure homogenization, wet grinding, ultrasonic homogenization . . or is carried out by a combination of such processes. In a further embodiment, the homogenization is performed in a plurality of homogenization steps. In a further embodiment, the appropriate particle size of vedacrine is , particles having an average size of less than 5 μm and a D90 of less than 6.5 μm. In a further embodiment, the appropriate particle size of vedacrine is particles having an average size of less than 2 μm and a D9 0 of less than 3 μm.

[0089] In another embodiment of the present invention, there is provided a method for preparing the composition of the present invention, comprising: (a) homogenizing a suspension of vedacrine, a non-ionic surfactant, and water to obtain a suspension containing an appropriate particle size of vedacrine; (b) adjusting the pH of the resulting suspension to a pH between pH 5.5 and pH 7 .5; (c) adjusting the sodium chloride concentration to an appropriate concentration; and (d) adjusting the osmolality to an appropriate level, wherein steps (b), (c), and (d) may be performed in the order of (b), (c), (d) ; (b), (d), (c); (c), (b), (d); (c), (d), (b); (d) ; (b), (c); or (d), (c), (b).

[0090] In another embodiment of the present invention, there is provided a method for preparing the composition of the present invention, comprising: (a) homogenizing a suspension of vedacrine and a non-aqueous liquid to obtain a suspension containing an appropriate particle size of vedacrine; (b) isolating the vedacrine; (c) adding the vedacrine to a non-ionic surfactant and water; (d) adjusting the pH of the resulting suspension to a pH between pH 5. 5 and pH 7.5; (e) adjusting the sodium chloride concentration to an appropriate concentration A method is provided that includes the step of adjusting to a degree, where steps (d) and (e) are May be performed in the order of (d), (e); or (e), (d).

[0091] In another embodiment of the present invention, a method for preparing a composition of the present invention, comprising: (a) The step of micronizing vedacillin to obtain vedacillin with an appropriate particle size, and (b) non-ionic A method is provided that includes adding vedacillin to water containing a surfactant, an appropriate concentration of sodium chloride, and adjusted to a pH between 5.5 and 7.5.

[0092] In another embodiment of the present invention, a pharmaceutical composition for dry powder inhalation, comprising vedacillin with an appropriate particle size, and a physiologically acceptable pharmacologically inert solid carrier, a physiologically acceptable A solid carrier containing a pharmacologically inert excipient, or a pharmaceutical composition comprising a mixture of physiologically acceptable pharmacologically inert excipients of one or more appropriate particle sizes is provided. In a preferred embodiment of this embodiment The solid carrier is selected from glucose, arabinose, maltose, saccharose, dextrose and lactose, and combinations thereof. Further In a preferred embodiment, the solid carrier is provided in the form of coarse particles having a mass median diameter between 50 μm and 500 μm. In yet another preferred embodiment, vedacillin is Provided in the form of micronized particles having a mass median aerodynamic diameter of less than 5 μm. In yet another Preferred embodiment, vedacillin is provided in the form of micronized particles having a mass median aerodynamic diameter between 1 μm and 3 μm.

[0093] In a further embodiment of the present invention, vedacillin with an appropriate particle size, or a pharmaceutically acceptable a salt or derivative that can be tolerated, and a physiologically acceptable pharmacologically inert excipient, or comprising a mixture of physiologically acceptable pharmacologically inert excipients of one or more suitable particle sizes A pharmaceutical composition for dry powder inhalation, wherein the particles of the composition correspond to a homogeneous composition and the homogeneous particles A pharmaceutical composition is provided in which the particles contain both bedaquiline and one or more excipients. In a preferred embodiment of the present embodiment, the particles have a mass median aerodynamic diameter of less than 5 μm. Further In another preferred embodiment, the particles have a mass median aerodynamic diameter between 1 μm and 3 μm In another preferred embodiment of the present embodiment, the excipient comprises a phospholipid or a combination of phospholipids In yet another preferred embodiment, the excipient comprises a salt. In a further preferred embodiment, the excipient comprises an amino acid or a combination of amino acids. In yet another preferred embodiment, the excipient comprises a sugar or a combination of sugars.

[0094] In another embodiment of the present invention, a dry powder inhaler device, a dry powder composition according to any of the embodiments of the dry powder composition described above in this specification and a pharmaceutical combination comprising means for introducing an inhalable dry powder composition into a patient's airway by inhalation are provided. In a preferred embodiment of the present embodiment, the dry powder inhaler device is a single-dose or multi-dose inhaler. In a further preferred embodiment, the dry powder inhaler device is pre-measured or measured by the device In another preferred embodiment, the pharmaceutical combination is intended for use in the treatment and / or prevention of lung infections caused by mycobacteria or other Gram-positive bacteria. In another preferred embodiment, the infection is non-tuberculous mycobacteria (no In another preferred embodiment, the pharmaceutical combination is intended for use in the treatment and / or prevention of lung infections caused by mycobacteria or other Gram-positive bacteria. In another preferred embodiment, the infection is non-tuberculous mycobacteria or other Gram-positive bacteria. In another preferred embodiment, the infection is non-tuberculous mycobacteria ntuberculosis mycobacteria) and Mycobacterium tuberculosis complex, and combinations thereof selected from the genus Mycobacterium species caused by. Another preferred embodiment, the non-tuberculous bacteria are Mycobacterium avium (Mycobacter ium avium), Mycobacterium intracellulare (Mycobacte rium intracellulare), Mycobacterium abscessus (My cobacterium abscessus), and Mycobacterium leprae, and combinations thereof selected from. Another preferred embodiment infection is cystic fibrosis, chronic obstructive pulmonary disease, or AIDS, such as Mycobacterium um avian complex pulmonary disease or non-tuberculous opportunistic infection with cystic fibrosis or chronic obstructive pulmonary disease in patients with opportunistic infections. Another preferred embodiment, the infection is non-tuberculous opportunistic mycobacteria in patients with cystic fibrosis infection.

[0095] In another embodiment of the present invention, a pharmaceutical composition according to any of the embodiments of the dry powder composition described herein provides for use in the treatment and / or prevention of pulmonary infections caused by mycobacteria or other gram-positive bacteria. In a preferred embodiment the pulmonary infection is non-tuberculous mycobacteria (nontuberculosis myc obacteria) and Mycobacterium tuberculosis (Mycobacterium tuberculos is) complex, and Mycobacterium (mycob is caused by a species of the genus Mycobacterium. In a preferred embodiment, nontuberculous mycobacteria (nontuberculosis mycobacteria) are Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium abscessus, and Mycobacterium leprae, and combinations thereof are selected. In another preferred embodiment, the infection is in a patient having cystic fibrosis, chronic obstructive pulmonary disease, or AIDS, such as Mycobacterium avian complex lung disease or nontuberculous opportunistic infection, and is an opportunistic infection associated with cystic fibrosis or chronic obstructive pulmonary disease. In another preferred embodiment, the infection is a nontuberculous opportunistic mycobacterial infection in a patient having cystic fibrosis. In another embodiment of the invention, when treating or providing prophylaxis against a lung infection caused by mycobacteria or other gram-positive bacteria, a system is intended for use in presenting antibiotic activity, the system comprising 1) a) a dry powder pharmaceutical formulation comprising a therapeutically effective amount of bedaquiline, b) one or more excipients selected from sugars, amino acids, and phospholipids, and combinations thereof, 2) a container for the formulation selected from a capsule or a blister package, and 3) a dry powder inhaler, wherein bedaquiline is presented in the form of a dry powder

[0096] and the bedaquiline-containing particles have a mass median diameter of from 1 μm to 5 μm. is provided.

[0097] ​​​​​​In another embodiment of the present invention, any of the embodiments of the dry powder composition described herein A composition that follows, wherein clofazimine or a pharmaceutically acceptable salt or derivative thereof, cefo xitin, amikacin, clarithromycin, pyrazinamide, rifampin, moxi floxacin (moxiflxacin), levofloxacin and para-aminosalicylic acid Salts, and a composition is provided that is administered before, simultaneously with, or after the administration of a drug selected from the mixtures thereof. In a preferred embodiment of this embodiment, the composition is clofazimine , or a pharmaceutically acceptable salt or derivative thereof, and amikacin, and mixtures thereof Is administered before, simultaneously with, or after the administration of a drug selected from. In another preferred Embodiment of this embodiment, the composition is administered before, simultaneously with, or after the administration of clofazimine . In another preferred embodiment of this embodiment, the composition is administered before, Simultaneously with, or after the administration of amikacin.

[0098] In another embodiment of the present invention, a combination according to any of the combinations of pharmaceutical dry powders described herein is provided, wherein the pharmaceutical combination provided herein is clofazimine Or a pharmaceutically acceptable salt thereof, cefoxitin, amikacin, clarithromycin , pyrazinamide, rifampin, moxifloxacin (moxiflxacin), levo Floxacin and para-aminosalicylic acid salts, and mixtures thereof are used to be administered before, simultaneously with, or after the administration of a drug selected from. In a preferred embodiment of this embodiment , the combination is clofazimine, or a pharmaceutically acceptable salt or derivative thereof, And amikacin, and before, simultaneously with, or after the administration of a drug selected from mixtures thereof . And amikacin, and before, simultaneously with, or after the administration of a drug selected from mixtures thereof It is used to be administered to. In another preferred embodiment of the present embodiment, the combination is Clofazimine, or a pharmaceutically acceptable salt or derivative thereof, and amikacin, and It is used to be administered before, simultaneously with, or after the administration of a drug selected from their mixtures In another preferred embodiment of the present embodiment, the combination is for the administration of clofazimine It is used to be administered before, simultaneously with, or after. In another preferred embodiment of the present embodiment In the form, the combination is used to be administered before, simultaneously with, or after the administration of amikacin It is used.

[0099] In a further embodiment of the present invention, in a patient in need thereof, mycobacteria ( mycobacteria) or a method for treating or preventing a lung infection caused by other Gram-positive bacteria Comprising the step of administering the composition of the present invention as described herein by inhalation A method is provided. In a preferred embodiment, the infection is non-tuberculous mycobacteria ( nontuberculosis mycobacteria) and Mycobacterium tuberculosis complex, and combinations thereof Selected from the genus Mycobacterium ( mycobacterium). In another preferred In an embodiment, it is a method of treatment or prevention, wherein the non-tuberculous mycobacterium ( nontuberculosis mycobacterium) is Mycobacterium Avium (Mycobacterium avium), Mycobacterium intracellulare Larale (Mycobacterium intracellulare), Mycobacterium Abscessus (Mycobacterium abscessus), and Mycobacterium leprae, and combinations thereof A method is provided that is selected from these. In another preferred embodiment, it is a method of treatment or prevention wherein the infection is an opportunistic infection selected from MAC lung disease and non-tuberculous infection in a patient having cystic fibrosis, chronic obstructive pulmonary disease or acquired immunodeficiency syndrome A method is provided. In another preferred embodiment, it is a method of treatment or prevention wherein the infection is a non-tuberculous opportunistic mycobacterial infection in a patient having cystic fibrosis A method is provided.

[0100] In another embodiment of the present invention, a method for treating or preventing a lung infection caused by mycobacteria or other Gram-positive bacteria in a patient in need thereof, wherein the administration of a drug selected from clofazimine or a pharmaceutically acceptable salt or derivative thereof, cefoxitin amikacin, clarithromycin, pyrazinamide, rifampin, moxifloxacin levofloxacin, and para-aminosalicylic acid salts, and mixtures thereof, is followed by or simultaneously with the administration of a composition according to the present invention as described herein by inhalation. In a preferred embodiment, the drug is clofazimine or amikacin. In another preferred embodiment, the drug is clofazimine

[0101] A powder suitable for use in a dry powder inhaler may consist of micronized agents formed by processes known in the art such as jet milling, high pressure homogenization or spray drying The drug may be delivered alone or with a pharmaceutical grade lactose (e.g., La ​​​​​ctohale (Registered Trademark), DFE Pharma, Veghel, Netherlands may be mixed with. The mixed preparation may contain a tertiary component such as magnesium stearate as a releasing agent (Jetzer et al., “Investigations on the Mechanism of magnesium stearate to modify aerosol performance in dry powder inhaled formulations”, J.Pharm Sci, 107(4)984 - 998, 2018). 107(4)984 - 998, 2018). 107(4)984 - 998, 2018).

[0102] The spray - dried particles may be 100% drug, or may contain one or more additional components to enhance the stability of the drug or the dispersibility of the powder. In one embodiment of the present invention, the additional component is a sugar, for example, but not limited to, trehalose, sucrose, lactose or fructose. Combinations of sugars can also be utilized. In another embodiment, the spray - dried particles of the present invention may contain one or more phospholipids. Specific examples of phospholipids include, but are not limited to, phosphatidylcholine, dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylethanolamine (DPPE), distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylglycerol (DPPG), or any combination thereof. In another embodiment, the particles may contain an amino acid. Specific examples of suitable amino acids include, but are not limited to, leucine and isoleucine. or any combination thereof. In another embodiment, the particles may contain an amino acid. Specific examples of suitable amino acids include, but are not limited to, leucine and isoleucine. or any combination thereof. In another embodiment, the particles may contain an amino acid. Specific examples of suitable amino acids include, but are not limited to, leucine and isoleucine. or any combination thereof. In another embodiment, the particles may contain an amino acid. Specific examples of suitable amino acids include, but are not limited to, leucine and isoleucine. dipalmitoylphosphatidylethanolamine (DPPE), distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylglycerol (DPPG), or any combination thereof. In another embodiment, the particles may contain an amino acid. Specific examples of suitable amino acids include, but are not limited to, leucine and isoleucine. or any combination thereof. Optionally, the particles may contain one or more sugars, one or more phospholipids, or one or more amino acids in addition to one or more sugars, one or more phospholipids, or one or more amino acids in addition to one or more sugars, one or more phospholipids, or one or more amino acids in addition to

[0103] Optionally, the particles may contain one or more sugars, one or more phospholipids, or one or more amino acids in addition to And it contains a small amount of strong electrolyte salts, such as, but not limited to, sodium chloride, sodium phosphate , sodium fluoride, sodium sulfate and calcium carbonate.

[0104] Suitable inhalers are described, for example, in U.S. Patent No. 4,069,819; U.S. Patent No. 4, 995,385; and U.S. Patent No. 5,997,848. As other examples, but not limited to, SPINHALER® (Fisons), ROTAHALER® (Glaxo-Wellcome), FLOWCAPS ® (Hovione), INHALATOR® (Boehring er Ingelheim), AEROLIZER® (Novartis) and also DISKHALER® (Glaxo-Wellcome), Plastia pe RS-01® and others known to those skilled in the art, etc. are included.

[0105] Particle size and distribution The therapeutic effect of aerosolized therapy depends on the deposited dose and its distribution. The aerosol particle size is one of the important variables in clarifying the deposited dose and distribution of the drug aerosol in the lungs .

[0106] Generally, inhaled aerosol particles are subject to deposition by one of two mechanisms, namely, impaction that is generally superior to larger aerosol particles and sedimentation that is generally superior to smaller aerosol particles. Impaction occurs when the momentum of the inhaled aerosol particles is large enough for the particles to encounter the physiological surface without following the airflow. In contrast, sedimentation is when the Mainly in the lower lungs, very small aerosol particles that move with the inhaled airflow are gravitationally sedimented and occur when they encounter the physiological surface as a result below.

[0107] Lung drug delivery may be achieved by inhalation of an aerosol through the mouth and pharynx. Aerosol particles having an aerodynamic diameter greater than about 5 μ m generally do not reach the lungs; instead they tend to affect behind the pharynx, are swallowed, and are probably absorbed orally. Aerosol particles having a diameter of about 3 μ m to about 5 μm are small enough to reach the upper to middle lung regions (to be transmitted through the airways ), but are too large to reach the alveoli. Smaller aerosol particles, i.e., about 0.5 to about 3 μm, have the ability to reach the alveolar region. Aerosol particles having a diameter smaller than about 0.5 μm tend to be exhaled during tidal breathing, but may also be deposited within the alveolar region by breath-holding.

[0108] Aerosols used in lung drug delivery are composed of a wide range of aerosol particle sizes and thus statistical descriptors are used. Aerosols used in lung drug delivery are typically described by their mass median diameter (MMD), i.e., half of the mass is contained in aerosol particles larger than the MMD and half of the mass is contained in aerosol particles smaller than the MMD. In the case of particles having a uniform density, the volume median diameter (VMD) can be used interchangeably with the MMD. Measurements of the VMD and MMD are made by laser diffraction. The width of the distribution is described by the geometric standard deviation (GSD). However, the deposition of aerosol particles in the airways is more accurately described by the aerodynamic diameter of the particles, and therefore, Typically, the mass median aerodynamic diameter is used. The measurement of MMAD is made by inertial impaction or flight time measurement. In the case of aqueous particles, VMD, MMD and MMAD need to be the same However, if the humidity is not controlled for the aerosol to pass through the impactor, the MMAD measurement value is due to dehydration and becomes smaller than MMD and VMD. Intended for this description The measurements of VMD, MMD and MMAD are considered to be under controlled conditions such that the descriptions of VMD, MMD and MMAD are equivalent to each other.

[0109] Nevertheless, intended for the description, the aerosol particle size of the aerosol is given as the MMAD when measured at room temperature using a Next Generation Impactor (NGI) in accordance with the United States Pharmacopeial Convention In Process Revision<601> Aerosols, Nasa l Sprays, Metered - Dose Inhalers, and Dry P owder Inhalers, Pharmacopeial Forum (2 003), Volume Number 29, pages 1176 - 1210 is also disclosed in J olyon Mitchell, Mark Nagel “Particle Size Analysis of Aerosols from Medicinal Inha lers”, KONA Powder and Particle Journal (2 004), Volume 22, pages 32 - 65. According to the present invention, the particle size of the aerosol maximizes the deposition at the infection site of bedaquiline and is resistant to

[0110] to It is optimized to maximize capacitance. The aerosol particle size may be represented in terms of the mass median aerodynamic diameter ( MMAD). Larger particles (e.g., MMAD > 5 μm) are too large to cause bending in the airways and tend to deposit in the extrapulmonary and upper airways. Non-tolerance (e.g., coughing and bronchospasm) may occur from the upper airway deposition of large particles.

[0111] Therefore, according to a preferred embodiment, the MMAD of the aerosol should be less than about 5 μm, preferably between about 1 - 5 μm, and more preferably less than 3 μm (<3 μm).

[0112] However, to allow larger particles to pass through the extrapulmonary and upper airways and deeper into the lungs than during ventilation breathing, and to increase the deposition of the aerosol in the central and lower lungs, an induced breathing method can be used. The induced breathing method may be as slow as about 100 mL / min. Thus, the preferred MMAD of the aerosol should be less than about 10 μm when used with the induced breathing method.

[0113] In the case of a suspension delivered by a nebulizer, (in addition to the aerosol particle size) an equally important factor is the particle size and size distribution of the solid particles, in this case the particle size and distribution of bedaquiline. The size of the solid particles in a given aerosol particle must be smaller than the aerosol particle in which it is contained. Larger aerosol particles may contain one or more solid particles. Further, when dealing with a dilute suspension, most of the aerosol particles may not contain solid particles. As a result, the drug is preferentially contained in the larger aerosol particles (e.g., Finlay, et al., “Predicting regional ​ Lung dosages of a nebulized suspension: P "Ulmicort (budesonide)", Particulate Science and Technology 15:243, 1997 (see).

[0114] Therefore, it is desirable to have solid drug particles that are significantly smaller than the MMAD of the aerosol particles. For example, when the MMAD of the aerosol particles is 3 μm, the desired solid particles will be 1 μm or less.

[0115] As a further consideration, for example, when using a vibrating mesh nebulizer, the formulation is pumped through an opening in the plate thereby breaking the suspension into droplets. Thus, the solid particles must also be smaller than these openings in order to pass through.

[0116] The solid particle size in the suspension may be given by the average size of the particles and further by the distribution of the particles. The D90 value indicates that 90% of the aerosol mass is contained in particles smaller than D90.

[0117] Nebulizer In the case of aqueous and other non-compressible liquid systems, various nebulizers (including metered dose inhalers) are available for aerosolizing the formulation. Compressor-driven nebulizers incorporate jet technology and use compressed air to generate liquid aerosols. Such devices are, for example, Healthdyne Technologies, Inc.; Invacare, Inc.; Mountain Medical Equipment, Inc.; Pari Res ​​​​Piratory, Inc.; Mada Medical, Inc.; Puritan- Bennet; Schuco, Inc., DeVilbiss Health Care , Inc.; and Hospitak, Inc. are commercially available. Ultrasonic nebulizers rely on mechanical energy in the form of vibrations of piezoelectric crystals to generate respiratory droplets. For example, they are commercially available from Omron Healthcare, Inc. and DeVilbiss Health C are, Inc. Vibration mesh nebulizers rely on either piezoelectric or mechanical pulses to generate respiratory droplets. Other examples of nebulizers contemplated for use with bedaquiline as described herein are U.S. Patent No. 4,268,460; U.S. Patent No. 4,0 46,146; U.S. Patent No. 4,649,911; U.S. Patent No. 4,624 ,251; U.S. Patent No. 5,164,740; U.S. Patent No. 5,586,5 50; U.S. Patent No. 5,758,637; U.S. Patent No. 6,644,304 ; U.S. Patent No. 6,338,443; U.S. Patent No. 5,906,202 ; U.S. Patent No. 5,934,272; U.S. Patent No. 5,960,792 ; U.S. Patent No. 5,971,951; U.S. Patent No. 6,070,575; U.S. Pat ent No. 6,192,876; U.S. Patent No. 6,230,706; U.S. Pat ent No. 6,349,719; U.S. Patent No. 6,367,470; U.S. Pat ent No. 6,543,442; U.S. Patent No. 6,584,971; U.S. Pat ent No. 6,601,581; U.S. Patent No. 4,263,907; U.S. Pat ent No. 5,70 9,202; U.S. Patent No. 5,823,179; U.S. Patent No. 6,192, 601,581; U.S. Patent No. 4,263,907; U.S. Patent No. 5,70 9,202; U.S. Patent No. 5,823,179; U.S. Patent No. 6,192, Specification No. 876; U.S. Patent No. 6,644,304; U.S. Patent No. 5,549,10 Specification No. 2; U.S. Patent No. 6,161,536; U.S. Patent No. 6,557,549 Specification; U.S. Patent No. 6,612,303; U.S. Patent No. 6,962,151 Specification; U.S. Patent No. 8,596,264; U.S. Patent No. 8,720,435; U.S. Patent No. 7,131,440; U.S. Patent No. 8,739,777; U.S. Patent No. 9,975,136; and U.S. Patent No. 8,387,895 (all of which are hereby incorporated by reference in their entirety); are described. As commercial examples of nebulizers in which the bedaquiline composition described in this specification can be used, Respirgard II (registered trademark), Aeroneb (registered trademark), Aeroneb (registered trademark) Pro, and Aeroneb (registered trademark) Go manufactured by Aerogen; ARx (registered trademark) and AERx Essence (trademark) manufactured by Aradigm; Porta-Neb (registered trademark), Freeway Freedom (trademark), Sidestream, Ventstream, and I-neb manufactured by Respironics, Inc.; and PARI LCPlus (registered trademark), PARI LC-Star (registered trademark), and e-Flow7m manufactured by PARI GmbH. Further non-limiting examples are disclosed in U.S. Patent No. 6,196,219. are hereby incorporated by reference in their entirety); are described. As commercial examples of nebulizers in which the bedaquiline composition described in this specification can be used, Respirgard II (registered trademark), Aeroneb (registered trademark), Aeroneb (registered trademark) Pro, and Aeroneb (registered trademark) Go manufactured by Aerogen; ARx (registered trademark) and AERx Essence (trademark) manufactured by Aradigm; Porta-Neb (registered trademark), Freeway Freedom (trademark), Sidestream, Ventstream, and I-neb manufactured by Respironics, Inc.; and PARI LCPlus (registered trademark), PARI LC-Star (registered trademark), and e-Flow7m manufactured by PARI GmbH. Further non-limiting examples are disclosed in U.S. Patent No. 6,196,219. According to the present invention, the pharmaceutical composition may preferably be aerosolized using a nebulizer selected from an ultrasonic nebulizer, an electronic spray nebulizer, a vibrating membrane nebulizer, a jet nebulizer, or a mechanical soft mist inhaler. Respirgard II (registered trademark), Aeroneb (registered trademark), Aeroneb (registered trademark) Pro, and Aeroneb (registered trademark) Go manufactured by Aerogen; ARx (registered trademark) and AERx Essence (trademark) manufactured by Aradigm; Porta-Neb (registered trademark), Freeway Freedom (trademark), Sidestream, Ventstream, and I-neb manufactured by Respironics, Inc.; and PARI LCPlus (registered trademark), PARI LC-Star (registered trademark), and e-Flow7m manufactured by PARI GmbH. Further non-limiting examples are disclosed in U.S. Patent No. 6,196,219. Respirgard II (registered trademark), Aeroneb (registered trademark), Aeroneb (registered trademark) Pro, and Aeroneb (registered trademark) Go manufactured by Aerogen; ARx (registered trademark) and AERx Essence (trademark) manufactured by Aradigm; Porta-Neb (registered trademark), Freeway Freedom (trademark), Sidestream, Ventstream, and I-neb manufactured by Respironics, Inc.; and PARI LCPlus (registered trademark), PARI LC-Star (registered trademark), and e-Flow7m manufactured by PARI GmbH. Further non-limiting examples are disclosed in U.S. Patent No. 6,196,219. ARx (registered trademark) and AERx Essence (trademark) manufactured by Aradigm; Porta-Neb (registered trademark), Freeway Freedom (trademark), Sidestream, Ventstream, and I-neb manufactured by Respironics, Inc.; and PARI LCPlus (registered trademark), PARI LC-Star (registered trademark), and e-Flow7m manufactured by PARI GmbH. Further non-limiting examples are disclosed in U.S. Patent No. 6,196,219. Porta-Neb (registered trademark), Freeway Freedom (trademark), Sidestream, Ventstream, and I-neb manufactured by Respironics, Inc.; and PARI LCPlus (registered trademark), PARI LC-Star (registered trademark), and e-Flow7m manufactured by PARI GmbH. Further non-limiting examples are disclosed in U.S. Patent No. 6,196,219. Porta-Neb (registered trademark), Freeway Freedom (trademark), Sidestream, Ventstream, and I-neb manufactured by Respironics, Inc.; and PARI LCPlus (registered trademark), PARI LC-Star (registered trademark), and e-Flow7m manufactured by PARI GmbH. Further non-limiting examples are disclosed in U.S. Patent No. 6,196,219. PARI LCPlus (registered trademark), PARI LC-Star (registered trademark), and e-Flow7m manufactured by PARI GmbH. Further non-limiting examples are disclosed in U.S. Patent No. 6,196,219. PARI LCPlus (registered trademark), PARI LC-Star (registered trademark), and e-Flow7m manufactured by PARI GmbH. Further non-limiting examples are disclosed in U.S. Patent No. 6,196,219. Further non-limiting examples are disclosed in U.S. Patent No. 6,196,219.

[0118] According to the present invention, the pharmaceutical composition may preferably be aerosolized using a nebulizer selected from an ultrasonic nebulizer, an electronic spray nebulizer, a vibrating membrane nebulizer, a jet nebulizer, or a mechanical soft mist inhaler. According to the present invention, the pharmaceutical composition may preferably be aerosolized using a nebulizer selected from an ultrasonic nebulizer, an electronic spray nebulizer, a vibrating membrane nebulizer, a jet nebulizer, or a mechanical soft mist inhaler. According to the present invention, the pharmaceutical composition may preferably be aerosolized using a nebulizer selected from an ultrasonic nebulizer, an electronic spray nebulizer, a vibrating membrane nebulizer, a jet nebulizer, or a mechanical soft mist inhaler.

[0119] Preferably, the device controls the patient's inhalation flow rate by either an electrical or a mechanical process. Preferably.

[0120] In a further preferred embodiment, aerosol generation by the device is caused by the patient's inhalation, for example, by an AKITA device. In a further preferred embodiment, aerosol generation by the device is caused by the patient's inhalation, for example, by an AKITA device.

[0121] Preferred (commercially available) examples of the nebulizer / device to be used according to the present invention include Vec tura fox, Pari eFlow, Pari Trek S, Philips Innospire mini, Philips InnoSpire Go, Meds pray device, Aeroneb Go, Aerogen Ultra, Res pironics Aeroneb, Akita, Medspray Ecomyst and Respimat.

[0122] Use in treatment and / or prophylaxis The pharmaceutical compositions, pharmaceutical combinations and systems according to the present invention are for the treatment and / or prophylaxis of lung infections caused by mycobacteria or other bedaquiline-susceptible bacteria, such as Staphylococcus aureus (including methicillin-resistant and vancomycin-intermediate-resistant strains), Streptococcus pneumoniae, and Enterococcus spp. The pharmaceutical compositions and pharmaceutical formulations of the present invention may also be used for the treatment and / or prophylaxis of pulmonary fungal infections. infections. infections.

[0123] Administration of bedaquiline According to the present invention, the pharmaceutical composition is delivered by spraying about 1 to 5 ml, preferably 1 to 2 ml of the pharmaceutical composition of the present invention.

[0124] Therefore, the target filling dose is about 1 to 5 ml corresponding to 20 to 100 mg of bedaquiline based on the concentration of bedaquiline in the pharmaceutical composition of about 20 mg / ml.

[0125] The daily lung dose (i.e., the dose deposited in the lung) of bedaquiline, either as a suspension from a nebulizer or as a dry powder from a dry powder inhaler, to be administered according to the present invention is about 5 to 10 mg, which corresponds to a nominal dose (device dose) of 15 to 30 mg in the case of M. abscessus infection.

[0126] It is understood by those skilled in the art that the lung dose of bedaquiline to be administered (and thus the filling / nominal dose / volume to be nebulized) can be routinely adjusted based on the MIC of bedaquiline in each bacterial strain well established in the art.

[0127] Depending on the dosing frequency, such as once or twice a day, the daily lung dose will be divided.

[0128] According to the present invention, bedaquiline should be administered once or twice a day with a resulting total daily lung dose of about 5 to 10 mg.

[0129] The above amounts relate to the free base of bedaquiline, and thus it will be apparent to those skilled in the art that the doses in the derivatives and salts need to be adjusted based on the MIC of each compound and strain.

[0130] Mucolytic / Biofilm Modifier To reduce sputum viscosity during aerosol treatment and to disrupt existing biofilms , the treatment and / or prophylaxis according to the invention may comprise an additional administration of a mucolytic agent and / or a biofilm disruptor.

[0131] These agents may be prepared in a fixed combination or may be administered simultaneously or subsequently to a pharmaceutical composition / aerosol formulation comprising bedaquiline according to the invention.

[0132] Agents for the dispersion / disruption of biofilms, mucolytics and / or mucoregulators, and / or agents for reducing biofilm formation to be used according to the invention are sprayed 4 -7% hypertonic saline, metaperiodic acid, sodium dodecyl sulfate, sodium bicarbonate, tromethamine, silver nanoparticles, bismuth thiol, ethylenediaminetetraacetic acid, gentamicin negatively charged phosphatidylcholine-modified gold nanoparticles, chelating agents, cis-2-decenoic acid, D-amino acids, D-enantiomeric peptides, gallium mesoporphyrin IX, gallium protoporphyrin IX, curcumin, patulin, penicillic acid, baicalein, naringenin, usolic acid, asiatic acid, corosolic acid, fatty acids, host defense peptides, and antibacterial peptides are selected from.

[0133] Furthermore, other pharmaceutically active agents may also be used in combination with the pharmaceutical composition / aerosol formulation according to the invention. Such active agents may be clofazimine or a pharmaceutically acceptable salt or derivative thereof, cefoxitin, amikacin, clarithromycin, pyrazinamide, rifampicin, moxifloxacin, levofloxacin, and para-aminosalicylic acid salts, and mixtures thereof.

[0134] These agents can be prepared in fixed combinations or administered before, simultaneously with, or after a pharmaceutical composition / aerosol formulation comprising bedaquiline according to the present invention.

[0135] The following examples more fully illustrate the manner of using the above invention and serve to show the best mode contemplated for carrying out the various aspects of the present invention. The examples according to the present invention fall within the scope of the claims herein.

Example

[0136] Experiment The following exemplary compositions and formulations were prepared according to the methods described herein.

[0137] Example 1 Preparation of Suspension Composition 1 A suspension was prepared to have the following composition: 500 mg of bedaquiline 2.5 ml of polysorbate 80 (NOF Corporation Hx2) 450 mg of sodium chloride 47.5 ml of water

[0138] At this point, when measured using Horiba LA950, the median size of the bedaquiline particles was 14.13 μm and the D90 was 103.48 μm.

[0139] Homogenization was initiated with a Polytron® immersion dispenser PT2500E (Kinematica, Luzern, Switzerland) and treated at 10,000 rpm for 2 × 5 minutes. Next, the resulting suspension was homogenized using a Branson digital sonifier - 250D, model 102C and treated at 70% on ice for 7 × 3 minutes. ​

[0140] The resulting suspension had a pH of 6 .91 and an osmolality of 341 mOsmol / kg when measured with a semi-micro osmometer K-7400 (Knauer).

[0141] The median size of the bedaquiline particles was measured to be 3.96 μm, D10 was 2.29 μm and D90 was 6.18 μm.

[0142] Determination of the minimum inhibitory concentration (MIC) Clinical and Laboratory Standards Insit According to the advice of the itute, a drug susceptibility test was performed. This was carried out by the micro-liquid dilution method in cation-adjusted Mueller-Hinton broth for Mycobacterium · abscessus, and also by the macro-liquid dilution method using BacTec 460 for Mycobacterium · avium. The MIC was determined by testing the susceptibility to the concentration of the composition of Example 1 between 0.05 μg / ml and 8 μg / m l. The results are shown in Table 2. M. avium B16079517 and M. abscessus B15012958 are clinical isolates. M. avium (M. avium) ATCC700898 and M. abscessus (M.abcessus ) CIP104536 are commercially available strains. (M. avium) ATCC700898 and M. abscessus (M.abcessus ) CIP104536 are commercially available strains. Species MIC (μg / ml) M. avium (ATCC700898) 0.03 M. avium (B16079517) 0.03 M. abscessus (CIP104536) 0.125 M. abscessus (B15012958) 0.5

[0143] These results indicate that the composition of Example 1 exhibits significant inhibitory activity against these mycobacteria ria).

[0144] Preparation of further compositions of bedaquiline A suspension of bedaquiline was prepared to have the following composition: 40 mg of bedaquiline 2.0 ml of polysorbate 80 (NOF Corporation Hx2) 360 mg of sodium chloride 398 ml of water

[0145] At this point, when measured using a Horiba LA950, the average size of the bedaquiline particles was 9.30 μm and the D90 was 10.97 μm.

[0146] Using an H30Z interaction chamber, this suspension was added to an M-110EH-30 Micr ofluidizer® processor. This suspension was recirculated at 4,400 psi for 5 minutes. At this point, the average size of the bedaquiline particles was 2.80 μm and the D90 was 4.41 μm.

[0147] A G10Z interaction chamber was installed and the above suspension obtained from the H30Z chamber was recirculated at 25,000 rpm and samples were collected after 10 minutes, 20 minutes and 35 minutes, and the following results were obtained: (1) After 10 minutes, the average size of the bedaquiline particles was 0.95 μm and the D90 was 2.08 μm; (2) After 20 minutes, the average size of the bedaquiline particles was 0.4 It was 6 μm, and D90 was 1.16 μm; and (3) after 35 minutes, the average size of the bedaquiline particles was 0.30 μm, and D90 was 0.79 μm. The pH of this sample after 35 minutes was 6.431, and the weight molar osmotic

[0148] concentration was 297 mOsmol / kg. The stability of the above suspension after 35 minutes was measured after standing for 17 days. The measurements carried out in three ways

[0149] showed that the average size of the bedaquiline particles was 0.37 μm and D90 was 0.96 μm. Cell viability The viability of lung epithelial cells was evaluated in the presence of a

[0150] bedaquiline suspension using two different cell types. The cell lines were A549 (DSMZ; ACC107) and Calu-3 (LGC Standards, ATCC-HTB-55). A549 cells were cultured in Roswell Park Memorial Institute medium (RPMI1640) + 10% fetal bovine serum (FCS), 1% penicillin / streptomycin (10,000 units / ml of penicillin; 10,000 units / ml of streptomycin) (Pen / Strep), and Calu-3 cells were cultured in minimum essential medium (Gibco by Life Technologies) (MEM) + 10% FCS, 1% non-essential amino acids 2 (additive for MEM), 1% sodium pyruvate, and 1% Pen / Strep. In normal cell culture, A549 and Calu-3 cells were passaged once a week at 80-90% Incubate with trypsin-EDTA for 5 minutes (A549) or with additional cell scraping for 1 5 minutes (Calu-3), then centrifuge the cells at 300 g for 5 minutes ( centrifuted). Resuspend the cell pellet in each cell culture medium. Count the cells using a Luna cell counter with 10 μl of stained cell suspension (18 μl of cell suspension + 2 μl of acridine orange, Live-Dead stain). In normal culture, seed 23 0,000 cells / flask (A549) or 1,300,000 cells / flask ( Calu-3) each into a new T175 cm 2 flask and culture at 37 °C in a 5% CO2 atmosphere.

[0151] MTT is the tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, which is converted by mitochondrial reductase to its insoluble formazan. In live cells, the insoluble formazan can be dissolved by adding the surfactant dimethyl sulfoxide for 15 minutes. The absorption of each dye is measured by a plate reader at 59 0 nm. Include positive and negative controls in the calculation of viability after incubation with the test compound. Use Hank's balanced salt solution (HBSS) as the negative control and set the resulting absorbance value to 100% viability. Use a positive control (1% Triton X100) and set it to 0% viability. Therefore, the IC50 value of the test formulation can be determined by measuring the dose-response curve on a logarithmic scale.

[0152] Next, prepare test samples against a suspension of bedaquiline and a medium without bedaquiline. ​

[0153] The formulation of vedacillin was prepared to contain 1 mg / ml of vedacillin, 0.5% of polysorbate 80, and 0.9% of sodium chloride in distilled water. The formulation without vedacillin was prepared to contain 0.5% of polysorbate 80 in distilled water or was prepared to contain 0.5% of polysorbate 80 and 0.9% of sodium chloride in water.

[0154] These formulations (designated as 100%) were diluted with HBSS to obtain the following test formulations.

[0155] Concentration of the vehicle solution Concentration (%) Vehicle solution (μl) HBSS (μl) 100 2000 0 95 1900 100 90 1800 200 85 1700 300 80 1600 400 70 1400 600 60 1200 800 50 1000 1000 Concentration of the vedacillin-containing suspension Concentration (%) Vedacillin (μl) Suspension HBSS (μl) Vedacillin (mg / ml) 100 2000 0 1 90 1800 200 0.9 80 1600 400 0.8 70 1400 600 0.7 60 1200 800 0.6 50 1000 1000 0.5 40 800 1200 0.4 30 600 1400 0.3 20 400 1600 0.2 10 200 1800 0.1 1 20 1980 0.01

[0156] The cells were treated with the test formulation at 37 °C for 4 hours. Using the viability of the cells after exposure, the dose response curve was set up on a logarithmic scale. The sigmoid fit enables the calculation of the IC2 0, IC50, and IC80 of the test substance. This is performed in the statistical program Origin( registered trademark) Pro2019.

[0157] Results A549 IC values Vedacillin suspension Medium solution IC20 90 - 95% 90 - 95% IC50 85 - 90% 85 - 90% IC80 80 - 85% 85 - 90% Calu-3 IC values Vedacillin suspension Medium solution IC20 95 - 100% 95 - 100% IC50 80 - 95% 95 - 100% IC80 60 - 70% 95 - 100%

[0158] These data indicate that vedacillin has the least cytotoxic effect on cell viability compared to the specific media tested. ​

Claims

1. (a) a therapeutically effective amount of bedaquiline, or a pharma- ceutically acceptable derivative or salt thereof; (b) a nonionic surfactant having a hydrophilic-lipophilic balance value greater than 10; and (c) an aqueous liquid carrier selected from water, isotonic saline, buffered saline, and aqueous electrolyte solutions; body wherein the bedaquiline or a pharma- ceutically acceptable derivative or salt thereof is in the form of a suspension. It is provided in the form of particles in and The particles of bedaquiline, or the particles of the pharma- ceutically acceptable salt of bedaquiline, are less than 5 μm in size. and a D90 of less than 6.5 μm. Pharmaceutical compositions.

2. The particles of bedaquiline, or the pharma- ceutically acceptable salt thereof, have a median size of less than 2 μm.

2. The pharmaceutical composition of claim 1, having a size and a D90 of less than 3 μm.

3. (a) a therapeutically effective amount of bedaquiline; (b) a nonionic surfactant having a hydrophilic-lipophilic balance value greater than 10; and (c) an aqueous liquid carrier selected from water, isotonic saline, buffered saline, and aqueous electrolyte solutions; body wherein the bedaquiline is provided in the form of particles in a suspension; and The bedaquiline particles have a median size of less than 5 μm and a D90 of less than 6.5 μm. R, Pharmaceutical compositions.

4. The bedaquiline particles have a median size of less than 2 μm and a D90 of less than 3 μm. The pharmaceutical composition according to claim 3.

5. The nonionic surfactant is polysorbate 20, polysorbate 60, polysorbate Hydrogenated stearyl alcohol having a hydrophilic-lipophilic balance value of 14-16. Polyethylene glycol derivatives of malt oil, with hydrophilic-lipophilic equilibrium values ​​of 15-17 Polyethylene glycol derivatives of chlorinated castor oil, sorbitan monolaurate, sorbitan Monopalmitate, sorbitan monostearate, polyoxyethylene (20) oleyl Ether, Polyoxyethylene (20) Cetyl Ether, Polyoxyethylene (10) Cetyl Ether ethyl ether, polyoxyethylene (10) oleyl ether, polyoxyethylene (1 (00) Stearyl ether, polyoxyethylene (10) Stearyl ether, polyoxyethylene Diethylene (20) stearyl ether, polyoxyethylene (4) lauryl ether, Polyoxyethylene (20) cetyl ether, polyoxyethylene (2) cetyl ether , Caprylocaproyl polyoxyl-8 glyceride, Polyethylene glycol monostearate Cole (20), polyethylene glycol stearate (40), polyethylene stearate Polyethylene glycol (100), polyethylene glycol stearate (8), and stearic acid 5. The composition according to claim 1, wherein the carboxylic acid is selected from the group consisting of polyoxyl 40, polyoxyethylene ... Item 1. The pharmaceutical composition according to item 1.

6. the non-ionic surfactant is polysorbate 80, and The aqueous liquid carrier is distilled water, hypertonic saline or isotonic saline; The pharmaceutical composition according to any one of claims 1 to 5.

7. 7. The method of claim 6, wherein the hypertonic saline is 1% to 7% (w / v) sodium chloride. Pharmaceutical composition.

8. The nonionic surfactant is ultra-pure polysorbate 80, and the aqueous liquid 7. The pharmaceutical composition of claim 6, wherein the carrier is isotonic saline.

9. The composition has an osmolality in the range of 200 to 700 mOsm / kg; The pharmaceutical composition according to any one of claims 1 to 8.

10. The composition has an osmolality in the range of 300 to 400 mOsm / kg; The pharmaceutical composition according to any one of claims 1 to 8.

11. The concentration of the non-ionic surfactant is in the range of 0.001% to 5% (v / v) of the total composition. Within, and the amount of bedaquiline is in the range of 0.1% to 20% (w / v) of the total composition; The pharmaceutical composition according to any one of claims 1 to 8.

12. (1) A suspension of bedaquiline, the non-aqueous suspension, and the like, in order to obtain a suspension containing bedaquiline of an appropriate particle size. homogenizing the ionic surfactant and water; (2) The pH of the suspension obtained from (1) is adjusted to a pH between pH 5.5 and pH 7.

5. a dividing step; (3) adjusting the sodium chloride concentration to an appropriate concentration; (4) adjusting the osmolality to an appropriate level; and The pharmaceutical composition according to any one of claims 1 to 11, which is prepared by a process comprising:

13. (1) A suspension of bedaquiline and a non-aqueous emulsion are mixed to obtain a suspension containing bedaquiline of an appropriate particle size. homogenizing the polymeric liquid; (2) isolating the bedaquiline; and (3) adding the bedaquiline to the non-ionic surfactant and water; (4) The pH of the suspension obtained from (3) is adjusted to a pH between pH 5.5 and pH 7.

5. a dividing step; (5) adjusting the sodium chloride concentration to an appropriate concentration; The pharmaceutical composition according to any one of claims 1 to 11, which is prepared by a process comprising:

14. (1) micronizing bedaquiline to obtain bedaquiline of a suitable particle size; (2) adding the bedaquiline to the non-ionic surfactant and water; (3) The pH of the suspension obtained from (2) is adjusted to a pH between pH 5.5 and pH 7.

5. a dividing step; (4) adjusting the sodium chloride concentration to an appropriate concentration; The pharmaceutical composition according to any one of claims 1 to 11, which is prepared by a process comprising:

15. In order to obtain a suitable particle size of bedaquiline, the non-ionic surfactant, the appropriate concentration of sodium chloride, In water containing thorium and adjusted to a pH between 5.5 and 7.

5.

12. The method of claim 1, wherein the method comprises the step of homogenizing a suspension of bedaquiline. The pharmaceutical composition according to any one of claims 1 to 5.

16. The pH was adjusted to 6.5 and the sodium chloride concentration was 154 mM sodium chloride.

14. A pharmaceutical composition prepared by the method of claim 12 or 13, wherein the pharmaceutical composition is adjusted to a normal range.

17. The pH was adjusted to 6.5 and the sodium chloride concentration was 154 mM sodium chloride.

15. A pharmaceutical composition prepared by the method of claim 14, wherein the pharmaceutical composition is adjusted to a pH of 10.

18. The pH is 6.5, and the appropriate concentration of sodium chloride is 154 mM sodium chloride.

16. A pharmaceutical composition prepared by the method of claim 15, wherein the compound is thorium.

19. The micronization of bedaquiline may be achieved by jet milling, spray drying, ball milling, or ultrafiltration.

15. A pharmaceutical composition prepared by the method of claim 14 carried out by supercritical fluid processing.

20. The homogenization in step (1) may be performed by high pressure homogenization, high shear homogenization, wet grinding, ultrasonic homogenization, etc. or a combination of such processes.

9. A pharmaceutical composition prepared by the method according to any one of claims 8 to 8.

21. 15. The method of claim 12, 13, or 15, wherein the homogenization of bedaquiline is carried out in multiple homogenization steps.

21. A pharmaceutical composition prepared by the method of any one of claims 16, 18 or 20.

22. The micronization of bedaquiline is carried out in multiple micronization steps.

20. A pharmaceutical composition prepared by the method according to any one of claims 19 to 20.

23. The suitable particle size of bedaquiline has an average size of less than 5 μm and a D90 of less than 6.5 μm. A pharmaceutical composition prepared by the method according to any one of claims 12 to 22, which is a particle having Pharmaceutical composition.

24. The suitable particle size of bedaquiline has an average size of less than 2 μm and a D90 of less than 3 μm. A pharmaceutical composition prepared by the method according to any one of claims 12 to 22, which is a particle Composition.

25. Ultrasonic nebulizer, electronic spray nebulizer, vibrating membrane nebulizer, jet nebulizer and mechanical soft 25. The method according to claim 1, wherein the inhaler is a nebulizer selected from the group consisting of the Tomist inhaler and the like. A pharmaceutical combination in the form of an inhalable aerosol prepared by aerosolization of the composition. There was, wherein the aerosol particles generated by the spray device have a mass median of 1 to 5 μm A pharmaceutical combination having a value aerodynamic diameter.

26. 26. The pharmaceutical combination of claim 25, wherein the inhalable aerosol is intended for deposition in the lower lung. Match.

27. Nebulized 4-7% hypertonic saline, metaperiodic acid, sodium dodecyl sulfate, sodium bicarbonate Lithium, Tromethamine, Silver Nanoparticles, Bismuththiol, Ethylenediaminetetraacetic acid, Gen tamycin-loaded phosphatidylcholine modified gold nanoparticles, chelating agent, cis-2-decenoic acid , D-amino acids, D-enantiomer peptides, gallium mesoporphyrin IX, gallium Muprotoporphyrin IX, curcumin, patulin, penicillic acid, baicalein, nari ursolic acid, asiatic acid, corosolic acid, fatty acids, host defense peptides, and and an antimicrobial peptide, , mucolytic and / or mucoactive agents, and / or agents that reduce biofilm formation The pharmaceutical composition according to any one of claims 1 to 24, which is to be used in combination with an agent.

28. Nebulized 4-7% hypertonic saline, metaperiodic acid, sodium dodecyl sulfate, sodium bicarbonate Lithium, Tromethamine, Silver Nanoparticles, Bismuththiol, Ethylenediaminetetraacetic acid, Gen tamycin-loaded phosphatidylcholine modified gold nanoparticles, chelating agent, cis-2-decenoic acid , D-amino acids, D-enantiomer peptides, gallium mesoporphyrin IX, gallium Muprotoporphyrin IX, curcumin, patulin, penicillic acid, baicalein, nari ursolic acid, asiatic acid, corosolic acid, fatty acids, host defense peptides, and and an antimicrobial peptide, , mucolytic and / or mucoactive agents, and / or agents that reduce biofilm formation 27. The pharmaceutical combination according to claim 25 or 26, which is to be used in combination with an agent.

29. Pulmonary infections caused by mycobacteria or other gram-positive bacteria A composition according to any one of claims 1 to 24, which is intended for use in the treatment and / or prevention of infections. The pharmaceutical composition described.

30. Pulmonary infections caused by mycobacteria or other gram-positive bacteria 27. A medicament according to claim 25 or 26, intended for use in the treatment and / or prevention of infections. combination.

31. The infection is caused by nontuberculosis mycobacteria. bacteria and Mycobacterium tuberculosis Mycobacterium sp. s complex, and combinations thereof.

30. The pharmaceutical composition contemplated for use according to claim 29, which is caused by the species of the genus Bacillus subtilis.

32. The infection is caused by nontuberculosis mycobacteria. bacteria and Mycobacterium tuberculosis Mycobacterium sp. s complex, and combinations thereof.

31. The pharmaceutical combination contemplated for use according to claim 30, which is caused by the species of the genus Pseudomonas bortezomib. 。

33. The nontuberculous mycobacteria eria is Mycobacterium avium m), Mycobacterium intracellulare (Mycobacterium int racellulare, Mycobacterium abscessus Mycobacterium abscessus, and Mycobacterium leprae e), and combinations thereof. Pharmaceutical composition.

34. The nontuberculous mycobacteria eria is Mycobacterium avium m), Mycobacterium intracellulare (Mycobacterium int racellulare, Mycobacterium abscessus Mycobacterium abscessus, and Mycobacterium leprae e), and combinations thereof. Drug combination.

35. The infection is in a patient with cystic fibrosis, chronic obstructive pulmonary disease or acquired immune deficiency syndrome.

31. The opportunistic infection in a patient in need thereof is selected from MAC pulmonary disease and nontuberculous infections. A pharmaceutical composition intended for use as described above.

36. The infection is in a patient with cystic fibrosis, chronic obstructive pulmonary disease or acquired immune deficiency syndrome.

32. The opportunistic infection in a patient in need thereof is selected from MAC pulmonary disease and nontuberculous infection.

2. A pharmaceutical combination as described above for use in a pharmaceutical composition according to claim 1.

37. The infection is a nontuberculous opportunistic mycobacterial infection in a patient with cystic fibrosis.

36. The pharmaceutical composition contemplated for use according to claim 35, wherein

38. The infection is a nontuberculous opportunistic mycobacterial infection in a patient with cystic fibrosis.

37. The contemplated use of the pharmaceutical combination according to claim 36,

39. Pulmonary infections caused by mycobacteria or other gram-positive bacteria Use in demonstrating antibiotic activity is contemplated when treating or providing prophylaxis against infection. A system in which 1) (a) a therapeutically effective amount of bedaquiline; (b) a nonionic surfactant having a hydrophilic-lipophilic balance value greater than 10; and (c) an aqueous liquid selected from water, isotonic saline, buffered saline, and aqueous electrolyte solutions; Carrier 1. A spray pharmaceutical formulation comprising and 2) Sprayer Including, wherein said bedaquiline is present in the form of a suspension; and The aerosol particles generated by the system have a mass median aerodynamic diameter of 1-5 μm having a target diameter, system.

40. 25, 26 or 2, wherein the spray device exhibits an output rate of 0.1 to 1.0 ml / min.

9. A pharmaceutical combination according to any one of claims 8.

41. Claims 30, 32 and 34, wherein the spray device exhibits an output rate of 0.1 to 1.0 ml / min.

39. A pharmaceutical combination as contemplated for use according to any one of claims 36 or 38.

42. 41. Any of claims 25, 26, 28 or 40, wherein the total inhalation volume is between 1 ml and 5 ml. A pharmaceutical combination according to any one of claims 1 to 4.

43. Claims 30, 32, 34, 36, 38, wherein the total inhalation volume is between 1 ml and 5 ml.

42. A pharmaceutical combination contemplated for use as defined in any one of claims 1 to 41.

44. Clofazimine or a pharma- ceutically acceptable salt or derivative thereof, cefoxitin, amine Kashin, clarithromycin, pyrazinamide, rifampin, moxifloxacin, levo of a drug selected from floxacin, and para-aminosalicylate, and mixtures thereof; The pharmaceutical composition contemplated for use according to claim 27 is administered prior to, simultaneously with or after administration of Composition.

45. Clofazimine or a pharma- ceutically acceptable salt or derivative thereof, cefoxitin, amine Kashin, clarithromycin, pyrazinamide, rifampin, moxifloxacin, levo of a drug selected from floxacin, and para-aminosalicylate, and mixtures thereof; 38. The method of claim 29, 31, 33, 35, or 37, which is administered before, simultaneously with, or after administration of A pharmaceutical composition intended for use as defined in any one of the claims.

46. Clofazimine or a pharma- ceutically acceptable salt or derivative thereof, cefoxitin, amine Kashin, clarithromycin, pyrazinamide, rifampin, moxifloxacin, levo of a drug selected from floxacin, and para-aminosalicylate, and mixtures thereof; The use according to claim 28 is intended to be used for administration before, simultaneously or after administration of Illustrated pharmaceutical combinations.

47. Clofazimine or a pharma- ceutically acceptable salt or derivative thereof, cefoxitin, amine Kashin, clarithromycin, pyrazinamide, rifampin, moxifloxacin, levo of a drug selected from floxacin, and para-aminosalicylate, and mixtures thereof; The compound according to claim 30, 32, 34, or 3 is used for administration before, simultaneously with, or after administration of the compound according to claim 30, 32, 34, or 3.

44. A pharmaceutical combination contemplated for use as defined in any one of claims 6, 38, 40 or 43.

48. 45. The pharmaceutical composition contemplated for use according to claim 44, wherein the drug is clofazimine. 。

49. 46. ​​The pharmaceutical composition contemplated for use according to claim 45, wherein the drug is clofazimine. 。

50. The intended use of the pharmaceutical combination according to claim 46, wherein the drug is clofazimine. Match.

51. The intended use of the pharmaceutical combination of claim 47, wherein the drug is clofazimine. Match.

52. 45. The pharmaceutical composition contemplated for use according to claim 44, wherein the agent is amikacin.

53. 46. ​​The pharmaceutical composition contemplated for use according to claim 45, wherein the drug is amikacin.

54. 47. The pharmaceutical combination contemplated for use according to claim 46, wherein said drug is amikacin. 。

55. 48. The pharmaceutical combination contemplated for use according to claim 47, wherein said drug is amikacin. 。

56. Mycobacteria or other infections in patients in need thereof A method for treating or preventing a pulmonary infection caused by a Gram-positive bacterium comprising administering to said patient a composition comprising the compound of any one of claims 1 to 24. A method comprising administering by inhalation a composition described in any one of claims 1 to 4.

57. The infection is caused by nontuberculosis mycobacteria. bacteria and Mycobacterium tuberculosis Mycobacterium sp. s complex, and combinations thereof.

57. The method of treatment or prevention according to claim 56, wherein the infection is caused by a species of the genus Lactobacillus oryzae.

58. The nontuberculous mycobacterium terium, Mycobacterium avium Mycobacterium intracellulare ntracellulare, Mycobacterium abscessus erium abscessus, and Mycobacterium leprae 58. The therapeutic or prophylactic method of claim 57, selected from the group consisting of cyclosporine, ... How to do it.

59. The infection is in a patient with cystic fibrosis, chronic obstructive pulmonary disease or acquired immune deficiency syndrome.

56. The opportunistic infection in a patient of claim 55, wherein the opportunistic infection is selected from MAC pulmonary disease and nontuberculous infection. The method for treatment or prevention described above.

60. The infection is a nontuberculous opportunistic mycobacterial infection in a patient with cystic fibrosis.

60. The method of treatment or prevention according to claim 59,

61. Mycobacteria or other infections in patients in need thereof A method for treating or preventing pulmonary infections caused by gram-positive bacteria comprising administering to said patient a therapeutically effective amount of clofazimine or its pharma- ceutically acceptable salt or derivative, cefoxitin, amikacin, clarithromycin mycin, pyrazinamide, rifampin, moxifloxacin, levofloxacin, and para-aminosalicylate, and mixtures thereof. A step of administering by inhalation a composition according to any one of claims 1 to 24 at or after A method, comprising:

62. 62. The treatment or prevention of claim 61, wherein the drug is clofazimine or amikacin. How to do it.

63. 63. A method of treatment or prevention according to claim 62, wherein the drug is clofazimine.

64. (1) A suspension of bedaquiline, said non-aqueous suspension, in order to obtain a suspension containing bedaquiline of an appropriate particle size, homogenizing the ionic surfactant and water; (2) The pH of the suspension obtained from (1) is adjusted to a pH between pH 5.5 and pH 7.

5. a dividing step; (3) adjusting the sodium chloride concentration to an appropriate concentration; (4) adjusting the osmolality to an appropriate level; and A method for preparing a pharmaceutical composition according to any one of claims 1 to 11, comprising:

65. (1) A suspension of bedaquiline and homogenizing the non-aqueous liquid; (2) isolating the bedaquiline; and (3) adding the bedaquiline to the non-ionic surfactant and water; (4) Adjusting the pH of the suspension obtained from (3) to a pH between 5.5 and 7.

5. and (5) adjusting the sodium chloride concentration to an appropriate concentration; A method for preparing a pharmaceutical composition according to any one of claims 1 to 11, comprising:

66. (1) micronizing bedaquiline to obtain bedaquiline of a suitable particle size; (2) adding the bedaquiline to the non-ionic surfactant and water; (3) The pH of the suspension obtained from (2) is adjusted to a pH between pH 5.5 and pH 7.

5. a dividing step; (4) adjusting the sodium chloride concentration to an appropriate concentration; A method for preparing a pharmaceutical composition according to any one of claims 1 to 11, comprising:

67. In order to obtain a suitable particle size of bedaquiline, the non-ionic surfactant, the appropriate concentration of sodium chloride, In water containing thorium and adjusted to a pH between 5.5 and 7.

5. The method according to any one of claims 1 to 11, comprising the step of homogenizing a suspension of bedaquiline. A method for preparing a pharmaceutical composition of

68. The pH was adjusted to 6.5 and the sodium chloride concentration was 154 mM sodium chloride.

68. The method of any one of claims 64, 65, or 67, wherein the concentration of α-aminobutyric acid in the blood is regulated by α-aminobutyric acid.

69. The pH is 6.5 and the suitable concentration of sodium chloride is 154 mM sodium chloride.

67. The method of claim 66, wherein the metal is thorium.

70. The micronization of the bedaquiline may be performed by jet milling, spray drying, ball milling, or 67. The method of claim 66, wherein the step of is carried out by supercritical fluid processing.

71. The homogenization may be performed by high pressure homogenization, wet milling, ultrasonic homogenization, or a combination of such processes.

69. The method of any one of claims 64, 65, 67 or 68, carried out by

72. The homogenization of bedaquiline is carried out in multiple homogenization steps. Claims 64, 65, 67, 68 or 71. The method of any one of claims 67, 68 or 71.

73. 66. The method of claim 66, wherein the micronization of bedaquiline is carried out in multiple micronization steps. 9 or 70. The method of any one of claims 9 or 70.

74. The suitable particle size of bedaquiline has an average size of less than 5 μm and a D90 of less than 6.5 μm. The method according to any one of claims 64 to 73, wherein the particle has the formula:

75. The suitable particle size of bedaquiline has an average size of less than 2 μm and a D90 of less than 3 μm. It is a particle that moves.

74. The method according to any one of claims 64 to 73.

76. (a) subjecting said non-aqueous suspension to a suspension containing bedaquiline of suitable particle size; (b) homogenizing the ionic surfactant and water; and (b) adjusting the pH of the resulting suspension to (c) adjusting the pH of said sodium chloride concentration to between pH 5.5 and pH 7.5; (d) adjusting the osmolality to an appropriate level. and adjusting the temperature of the sample, wherein steps (b), (c) and (d) are c), (d); (b), (d), (c); (c), (b), (d); (c), (d), ( b); (d), (b), (c); or (d), (c), (b), A method for preparing a pharmaceutical composition according to any one of claims 1 to 11.

77. (a) subjecting a suspension of bedaquiline to a suitable particle size; (b) homogenizing the non-aqueous liquid; (c) isolating the bedaquiline; (d) adding said bedaquiline to said non-ionic surfactant and water; (e) adjusting the pH of the suspension to a pH between pH 5.5 and pH 7.5; and adjusting the sodium chloride concentration to a suitable concentration, wherein step (d (e) may be performed in the order of (d), (e); or (e), (d). A method for preparing a pharmaceutical composition according to any one of claims 1 to 11.

78. (a) micronizing bedaquiline to obtain bedaquiline of a suitable particle size; b) containing the non-ionic surfactant, a suitable concentration of sodium chloride, and a pH of 5.5; adding said bedaquiline to water that has been adjusted to a pH between 7.5 and 8. A method for preparing a pharmaceutical composition according to any one of claims 1 to 11, comprising:

79. A pharmaceutical composition for dry powder inhalation, comprising bedaquiline, or a pharma- ceutical thereof, of suitable particle size. Acceptable salts or derivatives, and physiologically acceptable pharmacologically inactive excipients, or is a mixture of one or more suitable particle sizes of physiologically acceptable, pharmacologically inactive excipients. A pharmaceutical composition comprising:

80. A pharmaceutical composition for dry powder inhalation comprising bedaquiline of suitable particle size and a physiologically tolerable A pharmacologically inert solid carrier capable of carrying the compound, a physiologically acceptable pharmacologically inert excipient, A solid carrier comprising one or more suitable particle sizes of physiologically acceptable, pharmacologically inert A pharmaceutical composition comprising a mixture of excipients.

81. The solid carrier may be selected from the group consisting of glucose, arabinose, maltose, saccharose, and dextro.

81. The method of claim 79 or 80, wherein the saccharide is selected from the group consisting of saccharides and lactose, and combinations thereof. The composition described above.

82. The solid support is provided in the form of coarse particles having a mass median diameter between 50 and 500 μm. The composition according to any one of claims 79 to 81,

83. The bedaquiline is in the form of micronized particles having a mass median aerodynamic diameter of less than 5 μm.

83. The composition of any one of claims 79 to 82, wherein the composition is

84. The bedaquiline is in the form of micronized particles having a mass median aerodynamic diameter between 1 μm and 3 μm.

84. The composition of claim 83 provided in the form of a capsule.

85. The particles correspond to a homogenous composition and the particles contain bedaquiline and the one or more excipients.

80. The composition of claim 79, comprising both an

86. 86. The composition of claim 85, wherein the particles have a mass median aerodynamic diameter of less than 5 μm. Composition.

87. 85. The method of claim 84, wherein the particles have a mass median aerodynamic diameter between 1 μm and 3 μm.

86. The composition according to claim 86.

88. 88. Any of claims 85 to 87, wherein the excipient comprises a phospholipid or a combination of phospholipids. The composition according to any one of claims 1 to 4.

89. 88. The composition of any one of claims 85 to 87, wherein the excipient comprises a salt.

90. 88. Any of claims 85 to 87, wherein the excipient comprises an amino acid or a combination of amino acids. The composition according to any one of claims 1 to 4.

91. 88. The method of claim 85, wherein the excipient comprises a sugar or a combination of sugars. Composition of.

92. A dry powder inhaler, a dry powder composition according to any one of claims 79 to 91, and a means for introducing the inhalable dry powder composition into the respiratory tract of a patient by inhalation, combination.

93. 93. The method of claim 92, wherein the dry powder inhalation device is a single dose or a multi-dose inhaler. Pharmaceutical combinations.

94. 93. The dry powder inhalation device of claim 92, wherein the dry powder inhalation device is precalibrated or calibrated on the device. Pharmaceutical combinations.

95. Pulmonary infections caused by mycobacteria or other gram-positive bacteria 92. The composition according to any one of claims 79 to 91, which is intended for use in the treatment and / or prevention of infection. The pharmaceutical composition described in

96. Pulmonary infections caused by mycobacteria or other gram-positive bacteria 95. The composition according to any one of claims 92 to 94, which is intended for use in the treatment and / or prevention of infection. The pharmaceutical combination according to any one of claims 1 to 5.

97. The infection is caused by nontuberculosis mycobacteria. bacteria and Mycobacterium tuberculosis Mycobacterium sp. s complex, and combinations thereof.

96. The pharmaceutical composition of claim 95, wherein the compound is derived from a species of the genus Bacillus subtilis.

98. The infection is caused by nontuberculosis mycobacteria. bacteria and Mycobacterium tuberculosis Mycobacterium sp. s complex, and combinations thereof.

97. The pharmaceutical combination contemplated for use according to claim 96, which is caused by the species of the genus Pseudomonas bortezomib. 。

99. The nontuberculous mycobacteria eria is Mycobacterium avium m), Mycobacterium intracellulare (Mycobacterium int racellulare, Mycobacterium abscessus Mycobacterium abscessus, and Mycobacterium leprae e), and combinations thereof. Pharmaceutical composition.

100. The nontuberculous mycobacteria eria is Mycobacterium avium m), Mycobacterium intracellulare (Mycobacterium int racellulare, Mycobacterium abscessus Mycobacterium abscessus, and Mycobacterium leprae e), and combinations thereof. Drug combination.

101. The infection is in a patient with cystic fibrosis, chronic obstructive pulmonary disease or acquired immune deficiency syndrome.

97. The opportunistic infection in a patient of claim 97, wherein the opportunistic infection is selected from MAC pulmonary disease and nontuberculous infection. A pharmaceutical composition intended for use as described above.

102. The infection is in a patient with cystic fibrosis, chronic obstructive pulmonary disease or acquired immune deficiency syndrome.

98. The opportunistic infection in a patient of claim 97, wherein the opportunistic infection is selected from MAC pulmonary disease and nontuberculous infection.

2. A pharmaceutical combination as described above for use in a pharmaceutical composition according to claim 1.

103. The infection is a nontuberculous opportunistic mycobacterial infection in a patient with cystic fibrosis.

102. The pharmaceutical composition contemplated for use according to claim 101, wherein

104. The infection is a nontuberculous opportunistic mycobacterial infection in a patient with cystic fibrosis. The pharmaceutical combination of claim 102,

105. Pulmonary infections caused by mycobacteria or other gram-positive bacteria Use in demonstrating antibiotic activity is contemplated when treating or providing prophylaxis against infection. A system in which 1) (a) a therapeutically effective amount of bedaquiline; (b) one or more selected from sugars, amino acids, and phospholipids, and combinations thereof; The above excipients, 1. A dry powder pharmaceutical formulation comprising: 2) a container for the formulation selected from a capsule or a blister package; and 3) Dry powder inhaler wherein the bedaquiline is present in the form of a dry powder, and the bedaquiline-containing granules The children have a mass median diameter between 1 μm and 5 μm.

106. Clofazimine or a pharma- ceutically acceptable salt or derivative thereof, cefoxitin, amine Kashin, clarithromycin, pyrazinamide, rifampin, moxifloxacin, levo of a drug selected from floxacin, and para-aminosalicylate, and mixtures thereof; Administered prior to, simultaneously with or after said administration, according to claim 95, 97, 99, 101 or 1 03. A pharmaceutical composition according to any one of claims 03.

107. Clofazimine or a pharma- ceutically acceptable salt or derivative thereof, cefoxitin, amine Kashin, clarithromycin, pyrazinamide, rifampin, moxifloxacin, levo of a drug selected from floxacin, and para-aminosalicylate, and mixtures thereof; 96, 98, 100, which is used to administer the compound of claim 96, 98, 100, or 102 before, simultaneously with, or after administration of the compound of claim 96, 98, 100, 102 or 104. A pharmaceutical combination according to any one of claims 102 or 104.

108. 107. The pharmaceutical composition of claim 106, wherein the drug is clofazimine.

109. 108. The pharmaceutical combination of claim 107, wherein the drug is clofazimine.

110. 107. The pharmaceutical composition of claim 106, wherein the drug is clofazimine.

111. 107. The pharmaceutical composition of claim 106, wherein the agent is amikacin.

112. The pharmaceutical combination of claim 107, wherein the agent is amikacin.

113. Mycobacteria or other infections in patients in need thereof A method for treating or preventing a pulmonary infection caused by a Gram-positive bacterium comprising the steps of:

2. A method comprising administering by inhalation a composition described in any one of claims 1 to 10.

114. The infection is caused by nontuberculosis mycobacteria. bacteria and Mycobacterium tuberculosis Mycobacterium sp. s complex, and combinations thereof. The method of treatment or prevention according to claim 113, wherein the infection is caused by a species of the genus Lactobacillus oryzae.

115. The nontuberculous mycobacterium terium, Mycobacterium avium Mycobacterium intracellulare ntracellulare, Mycobacterium abscessus erium abscessus, and Mycobacterium leprae rae), and combinations thereof. How to do it.

116. The infection is in a patient with cystic fibrosis, chronic obstructive pulmonary disease or acquired immune deficiency syndrome.

12. The opportunistic infection in the lungs selected from MAC lung disease and nontuberculous infections in the lungs.

4. A method for treatment or prevention according to claim 3.

117. The infection is a nontuberculous opportunistic mycobacterial infection in a patient with cystic fibrosis. The method of treatment or prevention described in claim 116.

118. Mycobacteria or other infections in patients in need thereof A method for treating or preventing pulmonary infections caused by gram-positive bacteria comprising administering to said patient a therapeutically effective amount of clofazimine or its pharma- ceutically acceptable salt or derivative, cefoxitin, amikacin, clarithromycin mycin, pyrazinamide, rifampin, moxifloxacin, levofloxacin, and para-aminosalicylate, and mixtures thereof. At the same time or after the administration of a composition according to any one of claims 79 to 91 by inhalation. The method includes the steps of:

119. The therapeutic or prophylactic agent of claim 118, wherein the drug is clofazimine or amikacin. How to prevent it.

120. 120. A method of treatment or prevention according to claim 119, wherein the drug is clofazimine.

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