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

Abstract

To provide a system for delivering clofazimine to the lungs of a patient.SOLUTION: A system for use in providing antibiotic activity is provided including a dry powder inhalation device and a pharmaceutical composition. The pharmaceutical composition comprises clofazimine, or a pharmaceutically acceptable salt or derivative thereof, of one or more appropriate particle size, and a physiologically acceptable pharmacologically inert excipient, or a mixture of physiologically acceptable pharmacologically inert excipients of appropriate particle size or sizes. The clofazimine is provided in the form of finely divided particles having an aerodynamic mass median diameter of less than 5 μm.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 931,437, filed November 6, 2019, the contents of which are incorporated herein by reference.

[0002] The present invention relates to a pharmaceutical composition for inhalation comprising a therapeutically effective dose of clofazimine, wherein the clofazimine is provided in the form of a dry powder, to a process for its preparation, and to methods of use and treatment comprising the same. Furthermore, the present invention provides a pharmaceutical combination comprising clofazimine in the form of an aerosol for pulmonary inhalation.

[0003] The combinations and compositions provided by the present invention may be used in the treatment and / or prevention of pulmonary infections caused by mycobacteria and other gram-positive bacteria, as well as pulmonary fungal infections. [Background technology]

[0004] Clofazimine is a highly hydrophobic riminophenazine antibiotic (Log P=7.66) with antimycobacterial and anti-inflammatory activity that was first described in 1957. Its structural formula is: [ka]

[0005] The exact mechanism by which clofazimine exerts its antibacterial action is unknown; however, it is known to preferentially bind to mycobacterial DNA, thereby inhibiting DNA replication and cell proliferation. Other proposed mechanisms of action include membrane damage / destabilization, generation of membrane-destabilizing lysophospholipids, interference with potassium transport, and / or the intracellular redox cycle. Clofazimine is surprisingly active in vitro against Mycobacterium tuberculosis (MTB), including multidrug-resistant strains, but until recently, it was generally considered ineffective for the treatment of pulmonary tuberculosis (TB) (see, e.g., Cholo M et al., J Antimicrob Chemother, 2012 Feb, 67(2):290-8).

[0006] Clofazimine is one of the three main drugs recommended by the World Health Organization for the treatment of leprosy caused by Mycobacterium leprae and has recently been increasingly used for the treatment of other mycobacterial infections, such as drug-resistant tuberculosis and infections caused by nontuberculous mycobacteria (NTM).

[0007] Clofazimine is practically insoluble in water and exhibits high membrane permeability, making it a Class II drug in the Biopharmaceutics Classification System (BCS).

[0008] To overcome the problems associated with poor oral absorption and poor bioavailability of drugs, various strategies such as micronization, nanoparticle formation, supercritical fluid recrystallization, spray-freeze drying in liquid, solid dispersions, and solutions have been applied in optimizing oral dosage forms.

[0009] Clofazimine is classified as a BCS Class II drug and is therefore generally considered an ideal candidate for formulation into a solid dispersion for improved oral bioavailability (see, e.g., Bhusnure et al. IJRPC 2014, 4(4), 906-918).

[0010] Accordingly, due to its lipophilic nature, clofazimine is commonly administered as a microcrystalline suspension in an oil-wax base to improve oral absorption. Absorption in humans after oral administration is highly variable (45-62%). Adverse effects of clofazimine are dose-dependent and primarily affect the skin, eyes, gastrointestinal tract, and QT prolongation. Side effects include the development of reddish-brown discoloration of the skin and conjunctiva, which is gradually reversible upon discontinuation. These are the result of chronic systemic accumulation.

[0011] Mycobacteria are in the phylum Actinobacteria and their own family Mycobacteriaceae. Mycobacteria have a characteristic rod-shaped shape and a waxy outer coat. Therefore, mycobacteria can be divided into three groups: Mycobacterium tuberculosis complex - the causative agent of tuberculosis Mycobacterium leprae - the causative agent of leprosy Nontuberculous mycobacteria (NTM), which includes all other mycobacteria other than M. tuberculosis or M. leprae, including the Mycobacterium abscessus complex (MABSC) and the Mycobacterium avium complex (MAC).

[0012] Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. As one of the oldest documented human infectious pathogens, TB remains a significant cause of mortality and morbidity worldwide, with an estimated 10.4 million new cases of TB infection and 1.4 million deaths from active TB disease in 2015 (see, for example, the World Health Organization (WHO) Global Tuberculosis Report 2016). In addition to high morbidity and mortality, the incidence of multidrug-resistant tuberculosis (MDR-TB) is a growing concern, with 580,000 patients presenting with drug-resistant TB infection in 2015. Comorbidities, such as human immunodeficiency virus (HIV), complicate treatment and were involved in 1.2 million TB cases in 2015.

[0013] To treat multidrug-resistant (MDR) infections, the WHO recommends administering a 9-12 month treatment regimen of second-line anti-TB drugs. These regimens, e.g., 9-1 The 2-month Bangladesh regimen treats MDR-TB with a combination of gatifloxacin, ethambutol, pyrazinamide, and clofazimine, resulting in relapse-free cure in 87.9% of patients (see, e.g., Sotgiu, G, et al., "Applicability of the shorter 'Bangladesh regimen' in high multidrug-resistant tuberculosis"). settings”, International Journal of Infectious Diseases (2017) 56 190-193).

[0014] Other studies investigating shortened TB treatment have demonstrated that clofazimine has no clinical benefit after two weeks of oral administration (see, for example, Diacon, AH, et al., "Bactericidal Activity of Pyrazinamide and Clofazimine Alone and in Combinations with Pretomanid and Bedaquiline", American Journal of Respiratory and Critical Care Medicine (2015), 191(8), 943-953). The drug is thought to bind with high affinity to circulating serum proteins, and the lack of activity was attributed to the drug's low bioavailability. There, despite the fact that clofazimine has been empirically demonstrated to be effective in treating MDR-TB and extensively drug-resistant TB (XDR-TB), its low bioavailability after systemic administration appears to limit its biological activity for short-term therapy (see, for example, Swanson, RV, et al., "Pharmacokinetics and Pharmacodynamics of Clofazimine in a Mouse Model of Tuberculosis", Antimicrobial Agents and Chemotherapy (2015), 59(6), 3042-3051).

[0015] Treatment of pulmonary infections with inhaled antibiotics is known to result in higher drug concentrations in the lungs and reduced adverse effects compared to systemic delivery (see, for example, Touw, DJ, et al., "Inhalation of antibiotics in cystic fibrosis", European Respiratory Journal (1995), 8, 1594-1604), resulting in increased biological activity and efficacy (see, for example, Hickey, AJ, "Inhaled drug treatment for tuberculosis: Past progresses and future prospects", Journal of Controlled Release, (2016), 240, 127-134). In vivo mouse models have demonstrated that aerosolized clofazimine administration, compared with oral clofazimine, significantly improved clearance of bacilli in a TB infection model after only 28 days of treatment (see, e.g., Verma, RK, et al., "Inhaled microparticles containing clofazimine are efficacious in treatment of experimental tuberculosis in mice," Antimicrobial Agents and Chemotherapy (2013), 57(2), 1050-1052). This improved short-term efficacy is likely due to direct delivery of clofazimine to the site of infection in the lung, resulting in higher clofazimine concentrations in lung macrophages within tuberculous granulomas.

[0016] Therefore, the use of aerosolized clofazimine in patients with MDR TB or XDR-TB infection should further improve patient treatment outcomes and may shorten the duration of current treatment regimens.

[0017] The group of nontuberculous mycobacteria (NTM), formerly called atypical or ubiquitous mycobacteria, contains over 150 species. NTM are found ubiquitously in nature and can exhibit a wide diversity. They can be detected in soil, ground, and drinking water, as well as in foods such as pasteurized milk or cheese. NTM are generally considered to have low pathogenicity. Nevertheless, they can cause severe illness in humans, especially those with weakened immune systems or preexisting lung disease. Currently, NTM are classified according to their growth rate and are divided into slow-growing (SGM) and fast-growing (RGM) mycobacteria.

[0018] The slow-growing Mycobacterium avium complex (MAC) includes the most important and most frequently pathogenic species of NTM: Mycobacterium avium, Mycobacterium chimaera, and Mycobacterium intracellulare. Other species include Mycobacterium kansasii, Mycobacterium malmoense, Mycobacterium xenopi, Mycobacterium simiae, and Mycobacterium abscessus. abscessus, Mycobacterium gordonii These, along with Mycobacterium gordonae, Mycobacterium fortuitum, and Mycobacterium chelonae, mostly cause pulmonary infections. Mycobacterium marinum is involved in skin and soft tissue infections such as aquarium granulomas.

[0019] In particular, RGM causes severe, life-threatening chronic lung disease and is involved in disseminated and often fatal infections. Infection is usually caused by contaminated materials and invasive procedures, including catheters, non-sterile surgical procedures or injections, and the implantation of foreign bodies. Exposure to showerheads and whirlpools has also been reported to be a risk of infection. NTM usually causes opportunistic infections in patients with chronic lung diseases such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and other immunocompromised patients.

[0020] In recent years, the rapid-growing (RGM) Mycobacterium abscessus complex (MABSC), which includes the subspecies Mycobacterium abscessus subsp. abscessus (Maabscessus), Mycobacterium abscessus bolletii, and Mycobacterium abscessus massiliense, has emerged as an important human pathogen, associated with a significantly higher case fatality rate than any other RGM.

[0021] Mycobacterium abscessus infections in CF patients are particularly problematic because they lead to enhanced lung destruction and are often untreatable, with failure rates of 60-66% (e.g., Obregon-Henao A et al, Antimicrobial Agents and Chemotherapy, November 2015, Vol 59, No 11, p. 6904-6912; Qvist, T., Pressler, T., Hoiby, N. and Katzenstein, T.L., “Shifting paradigms of nontuberculous mycobacteria in cystic fibrosis”, Respiratory Research (2014), 15(1): pp.41-47).

[0022] Human infections with NTM have become increasingly associated with the emergence of epidemics of human acquired immunodeficiency syndrome (HIV). 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).

[0023] Some NTM species are known to form biofilms, which are microcolonies of bacteria embedded in an extracellular matrix, providing stability and resistance to human immune systems. Recently, some NTM species have been shown to form biofilms that enhance resistance to disinfectants and antibacterial agents. Biofilm construction involves several stages, including reversible attachment, irreversible attachment, biofilm formation by bacterial aggregation, organization, and signaling, and finally dispersal. During this process, bacteria develop a matrix containing extracellular polymeric substances (EPS), such as polysaccharides, lipids, and nucleic acids, forming a complex three-dimensional structure (see, for example, Sousa S. et al., International Journal of Mycobacteriology 4 (2015), 36-43). Specifically, mycobacterial EPS differs from other biofilms because mycobacteria do not produce exopolysaccharides (see, e.g., Zambrano MM, Kolter R. Mycobacterial biofilms: a greasy way to hold it together. Cell. 2005). Mycobacterial biofilms vary between species but can contain mycolic acids, glycopeptidolipids, mycolyl-diacylglycerol, lipooligosaccharides, lipopeptides, and extracellular DNA (Rose SJ, Babrak LM, Bermudez LE (2015) Mycobacterium avium Possesses Extracellular DNA that Contributes to Biofilm Formation, Structural Integrity, and Tolerance to Antibiotics. Review and original research from PLoS ONE). Biofilm organization is known to enhance resistance to antimicrobial agents (see, e.g., Faria S. et al., Journal of Pathogens, Vol 2015, Article ID 809014).

[0024] Delivery of aerosolized liposomal amikacin / inhalation of amikacin solution nebulized by a jet nebulizer (Rose et al., 2013) as a novel approach for the treatment of NTM pulmonary infections. S. et al., 2014, PLoS ONE, Volume 9, Issue 9, e108703, and Olivier K. et al., Ann Am Thorac Soc Vol 11, No 1, pp. 30-35), as well as inhalation of dry powder microparticles of anti-TB drugs for pulmonary delivery (Cholo M et al., J Antimicrob Chemother. 2012 Feb;67(2):290-8 and Fourie B. and Nettey O., 2015 Inhalation Magazine, Verma 2013 Antimicrob Agents Chemother) have been proposed.

[0025] Multiple combination regimens involving initial treatment with parenteral aminoglycosides, tigecycline, and other promising oral antibiotics, such as linezolid, delamanid, and bedaquiline, followed by inhaled amikacin and, in selected cases, surgical intervention, have shown promising results in the treatment of NTM lung disease (Lu Ryu et al., Tuberc Respir D is 2016;79:74-84). However, the increasing incidence and prevalence of NTM infections, especially NTM pulmonary disease, and limited treatment options necessitate the development of novel dosage forms / pharmaceutical formulations that increase the bioavailability of currently used antibiotics, such as clofazimine. Compared with oral and parenteral treatments, inhalation may enhance efficacy and reduce adverse effects.

[0026] The combination of clofazimine and amikacin has been shown to act synergistically in vitro against both Mycobacterium abscessus and Mycobacterium avium (see, e.g., van Ingen, J., et al., "In Vitro Synergy between Clofazimine and Amikacin in Treatment of Nontuberculous Mycobacterial Disease," Antimicrobial Agents and Chemotherapy 56(12), 6324-6327 (2012)). Additionally, a synergistic effect has been demonstrated with the combination of clofazimine and bedaquiline used against Mycobacterium tuberculosis (see, e.g., Cokol, M. et al., “Efficient Measurement and Factorization of High-Order Drug Interactions in Mycobacterium tuberculosis,” Sciences Advances 2017:3:e170881, 11 October 2017). A synergistic effect has also been demonstrated with the combination of clofazimine and bedaquiline against the non-tuberculous bacterium Mycobacterium abscessus (Ruth, MM et al., “A Bedaquiline / Clofazimine Combination Regimen Might Add Activity to the Treatment of Clinically Relevant Non-Tuberculous Mycobacteria”, Journal of Antimicrobial Chemotherapy (2019), doi.org / 10.1093 / jac / dky526).

[0027] Fungal pathogens have emerged as a leading cause of human mortality. Current estimates suggest that deaths from invasive fungal infections are comparable to those of more well-known infectious diseases such as tuberculosis. Candida albicans, Cryptococcus neoformans, and Aspergillis fumigatus represent the most prevalent human fungal pathogens. Each of these species is responsible for hundreds of thousands of infections annually, and mortality rates are unacceptably high due to poor diagnosis and limited treatment options. Clofazimine has been shown to be effective as a combination drug against multiple fungi (see, e.g., Robbins, N., et al., "An Antifungal Combination Matrix Identifies a Rich Pool of Adjuvant Molecules that Enhance Drug Activity against Diverse Fungal Pathogens," Cell Reports 13, 1481-1492, November 17, 2015). Fungi also play a role as commensals, colonizers, and / or pathogens in cystic fibrosis (see, e.g., Chotirmall, SH and McElvaney, NG, "Fungi in the cystic fibrosis lung: Bystanders or pathogens?", The International Journal of Biochemistry & Cell Biology 52 (2014), 161-173). Summary of the Invention [Means for solving the problem]

[0028] According to one aspect of the present invention, pulmonary mycobacterial infections are treated with clofazimine delivered directly to the lungs by oral inhalation, with the dose delivered to the patient being lower than the corresponding oral dose.

[0029] One aspect of the present invention is to deliver between 10 and 20 mg of clofazimine to the patient's lungs. The clofazimine can be in the form of a neat drug or a pharmaceutically acceptable derivative or salt.

[0030] There are several embodiments that can be used to deliver said amount of drug to a patient by aerosol. One embodiment is a dry powder inhaler.

[0031] Those skilled in the art can envision numerous embodiments that are described slightly differently but still have the same therapeutic effect of delivering between 10 mg and 20 mg of clofazimine to the lungs. 1. Alternative forms of clofazimine: Powders may be manufactured using pharmaceutically acceptable derivatives, polymorphs, or salts of clofazimine. 2. Use of Alternative Inhalers: The formulations may be adapted for use with any dry powder inhaler, including other capsule-based devices, blister strip inhalers, reservoir inhalers, disposable inhalers, and reusable inhalers. 3. Alternative particle size: Each inhaler has a different resistance to airflow, with inhalers with higher resistance resulting in lower inhalation flow rates. Selecting an inhaler with higher resistance (lower inhalation flow rates) allows for the use of larger particle sizes (up to 10 μm) for effective pulmonary delivery. 4. Alternative formulation components: Many grades of lactose, differing in size and geometry, are available for use in inhalation formulations. Small lactose particles can also be preblended to aid dispersion. Lactose can be replaced by a physiologically acceptable, pharmacologically inert solid carrier. Additional excipients, such as phospholipids, salts, surfactants, or polymers, can be added to aid aerosol dispersion. 5. Alternative Formulations: Alternatively, clofazimine and excipients may be dissolved in one or more solvents and spray dried.

[0032] Aerosolization of the compositions of the present invention by a suitable inhaler results in significantly increased delivery of aerosolized clofazimine to the lower lung (i.e., the bronchi, bronchioles, and alveoli in the central and lower lung periphery), thereby substantially improving therapeutic efficacy.

[0033] Furthermore, the inhalation device should preferably also be adapted for local pulmonary delivery of an aerosol with a particle size distribution optimal for uniform deposition in the lower lung.

[0034] The present invention therefore provides aerosols having aerosol particles sized to facilitate delivery to the alveoli and bronchioles. A suitable aerodynamic particle size for targeting the alveoli and bronchioles is between 1 and 5 μm. Larger particles are preferentially deposited in the upper lung, i.e., the bronchi and trachea, and the mouth and pharynx, i.e., the oropharyngeal region. Thus, the inhalation device is adapted to generate aerosols having a mass median aerodynamic diameter (MMAD) in the range of about 1 to about 5 μm, preferably about 1 to about 3 μm. In a further embodiment, the particle size distribution is narrow, with a geometric standard deviation (GSD) of less than about 2.5. DETAILED DESCRIPTION OF THE INVENTION

[0035] The present invention provides a novel method for the pulmonary aerosol administration of clofazimine, which can achieve lower (i.e., deeper) lung deposition of the active agent, thereby significantly increasing the bioavailability of highly hydrophobic BCS Class II drugs, resulting in reduced systemic side effects and This is based on the unexpected discovery that there is an associated significant increase in therapeutic efficacy.

[0036] In another aspect, this finding provides improved antibiotic therapy for infections caused by mycobacteria and gram-positive bacteria, particularly pulmonary infections by NTMs such as cystic fibrosis, chronic obstructive pulmonary disease, and opportunistic infections in immunocompromised patients, e.g., HIV patients.

[0037] Furthermore, the present invention aims to overcome the systemic side effects of established oral treatment regimens for pulmonary infections by Gram-positive bacteria, particularly pulmonary TB and NTM infections, and to reduce the dose and duration of treatment with clofazimine.

[0038] It will be understood by those skilled in the art that the present application also discloses each and every individual feature disclosed herein and any combination thereof.

[0039] definition The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the compounds of the present invention and is not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids that can form salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids from which salts can be formed include, for example, acetic acid, propionic acid, naphtoic acid, oleic acid, palmitic acid, pamo (emboic acid), stearic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, ascorbic 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, and the like.

[0040] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases that can form salts include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum, with ammonium, potassium, sodium, calcium, and magnesium salts being particularly preferred. Organic bases that can form salts include, for example, primary, secondary, and tertiary amines, substituted amines, such as naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, specifically, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, histidine, arginine, lysine, benethamine, N-methyl-glucamine, and ethanolamine. Other acids include dodecylsulfuric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, and saccharin.

[0041] According to the invention, apart from the free base, the use of salts of methanesulfonic acid, maleic acid, isonicotinic acid, nicotinic acid, malonic acid and salicylic acid, and in particular clofazimine mesylate, is preferred.

[0042] The term "pharmaceutically acceptable derivatives" as used herein refers to compounds disclosed, for example, in U.S. Pat. No. 9,540,336, the disclosure of which is incorporated herein by reference in its entirety. In addition, derivatives may be those described in Lu, Y., Zhen, M., Wang, B., Fu, L., Zhao, W., Li, P., Xu, J., Zhu, H., Jin, H., Yin, D., Huang, H., Upton, A. M., and Ma, Z., "Clofazimine Analogs with "Efficacy against experimental tuberculosis and reduced potential for accumulation" in Antimicrobial Agents and Chemotherapy (2011), 55(11): pp. 5185-5193. Furthermore, the term "pharmaceutically acceptable derivative" of a compound is, for example, a prodrug of said compound. Generally, a prodrug is a derivative of a compound that is capable of providing the active form of the compound upon administration. Such a derivative can be, for example, an ester or amide of a carboxyl group, a carboxyl ester of a hydroxyl group, or a phosphate ester of a hydroxyl group.

[0043] "Patient" means a mammal, preferably a human, in need of prevention and / or treatment as described herein.

[0044] "Therapeutically effective amount," "therapeutically effective dose," or "pharmaceutically effective amount" refers to an amount of clofazimine, or a pharmaceutically acceptable salt or derivative thereof, disclosed for this invention, that has a therapeutic effect. The dose of clofazimine useful in treatment is a therapeutically effective amount. Thus, as used herein, a therapeutically effective amount refers to the amount of clofazimine that produces the desired therapeutic effect as determined by clinical trial results and / or model animal infection studies.

[0045] The amount and daily dose of clofazimine can be routinely determined by those skilled in the art and may vary depending on several factors, such as the specific microbial strain involved. This amount may further depend on the patient's height, weight, sex, age, and medical history. In the case of prophylactic treatment, a therapeutically effective amount is an amount that is effective for preventing microbial infection.

[0046] A "therapeutic effect" alleviates to some extent one or more symptoms of an infection, including curing the infection. "Cure" means that the symptoms of an active infection are eliminated, including complete or substantial elimination of excess members of the viable microorganisms involved in the infection to a point below the threshold of detection by conventional measurements. However, certain long-term or permanent effects of the infection may persist even after a cure is achieved (e.g., extensive tissue damage). As used herein, "therapeutic effect" is defined as a statistically significant reduction in bacterial burden in the host, emergence of resistance, or improvement in infection symptoms, as measured by human clinical results or animal studies.

[0047] As used herein, "treat," "treatment," or "treating" refers to administering a pharmaceutical composition / combination for prophylactic and / or therapeutic purposes.

[0048] The terms "prophylactic treatment" or "prevention" refer to treating a patient who is not yet infected but who is susceptible to or otherwise at risk of a particular infection. The term "therapeutic treatment" refers to administering treatment to a patient who already suffers from an infection. Thus, in a preferred embodiment, treatment is the administration of a therapeutically effective amount of clofazimine to a mammal (for either therapeutic or prophylactic purposes).

[0049] Unless otherwise stated herein, the term "inhalation" is meant to refer to pulmonary inhalation.

[0050] Unless otherwise stated herein, the term "infection" as used herein is meant to refer to a pulmonary infection.

[0051] Unless otherwise stated, "substantially" when used to refer to the purity of a compound The term indicates a purity of the compound of 95% or greater purity.

[0052] Unless otherwise stated, the term "appropriate particle size" refers to the particle size of clofazimine in the composition, i.e., the composition that provides the desired therapeutic effect when administered to a patient.

[0053] Unless otherwise stated, the term "appropriate concentration" refers to the concentration of ingredients in a composition or combination that provides a pharmaceutically acceptable composition or combination.

[0054] Pharmaceutical Compositions and Combinations Clofazimine has been shown to exist in at least four polymorphic forms (see, e.g., Bannigan, et al., "Investigation into the (See "Solid and Solution Properties of Known and Novel Polymorphs of the Antimicrobial Molecule Clofazimine", Cryst. Growth Des. 2016, 16(12), pp. 7240-7250). Clofazimine can exist in the triclinic form FI, the monoclinic form FII, and the orthorhombic form FIII. An additional form, FIV, has also been observed, but only at elevated temperatures.

[0055] Thus, in a further embodiment of the present invention, (a) a therapeutically effective dose of clofazimine A pharmaceutical composition comprising: wherein the clofazimine is provided in the form of a dry powder particle, The particles of clofazimine have a median diameter of less than 5 μm and a D90 of less than 6 μm, preferably a median diameter of less than 2 μm and a D90 of less than 3 μm, and the clofazimine is provided in a polymorphic form or a form selected from triclinic form FI, monoclinic form FII and orthorhombic form FIII, and mixtures of such forms. In a preferred embodiment, the clofazimine is provided substantially in orthorhombic form FIII.

[0056] In another embodiment, there is provided a pharmaceutical composition according to any one of the embodiments of the compositions described herein, for use in combination with an agent for dispersing and / or disrupting biofilms and an agent that reduces biofilm formation selected from a mucolytic and / or mucoactive agent, and / or metaperiodate, sodium dodecyl sulfate, sodium bicarbonate, tromethamine, silver nanoparticles, bismuth thiol, ethylenediaminetetraacetic acid, gentamicin-loaded phosphatidylcholine-modified gold nanoparticles, a chelating agent, cis-2-decenoic acid, D-amino acids, D-enantiomeric 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 antimicrobial peptides. In another embodiment, the composition for said use is administered before, concurrently with, or after the administration of a drug selected from bedaquiline or a pharmaceutically acceptable salt or derivative thereof, cefoxitin, amikacin, clarithromycin, pyrazinamide, rifampin, moxifloxacin, levofloxacin, and para-aminosalicylates, and mixtures thereof.

[0057] In another embodiment, a pharmaceutical combination according to any of the combination embodiments described herein comprises an agent for dispersing and / or disrupting a biofilm and a mucolytic and / or mucoactive agent, and / or a compound selected from the group consisting of metaperiodate, 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-enantiomeric peptides, gallium mesoporphyrin IX, gallium protoporphyrin IX, curcumin, patulin, penicillic acid, baicalein, nar ... A pharmaceutical combination for use in combination with an agent that reduces biofilm formation selected from genin, ursolic acid, asiatic acid, corosolic acid, fatty acids, host defense peptides, and antimicrobial peptides is provided. In another embodiment, the combination for use is used to administer a composition of the present invention before, simultaneously with, or after administration of an agent selected from bedaquiline or a pharmaceutically acceptable salt or derivative thereof, cefoxitin, amikacin, clarithromycin, pyrazinamide, rifampin, moxifloxacin, levofloxacin, and para-aminosalicylates, and mixtures thereof. In another embodiment, the composition is administered before, simultaneously, or after administration of an agent selected from bedaquiline or a pharmaceutically acceptable salt or derivative thereof, and amikacin, and mixtures thereof. In a further embodiment, the composition is administered before, simultaneously, or after administration of bedaquiline or a pharmaceutically acceptable salt or derivative thereof.

[0058] In another embodiment, a pharmaceutical composition according to any one of the composition embodiments described herein is provided for use in the treatment and / or prevention of pulmonary infections caused by mycobacteria or other Gram-positive bacteria. In a further embodiment, the infection is caused by a Mycobacterium species selected from nontuberculous mycobacteria and the Mycobacterium tuberculosis complex, and combinations thereof. In a further embodiment, the nontuberculous mycobacteria is Mycobacterium avium. avium, Mycobacterium intracellulare, Mycobacterium abscessus, and Mycobacterium leprae, and combinations thereof. In another embodiment, the infection is an opportunistic infection selected from MAC pulmonary disease and nontuberculous infections in patients with cystic fibrosis, chronic obstructive pulmonary disease, or acquired immunodeficiency syndrome. In another embodiment, the infection is an opportunistic nontuberculous mycobacterial infection in patients with cystic fibrosis. In another embodiment, the composition for the above use is administered before, concurrently with, or after administration of a drug selected from bedaquiline or a pharmaceutically acceptable salt or derivative thereof, cefoxitin, amikacin, clarithromycin, pyrazinamide, rifampin, moxifloxacin, levofloxacin, and para-aminosalicylates, and mixtures thereof. In another embodiment, the composition is administered before, concurrently with, or after administration of an agent selected from bedaquiline or a pharmaceutically acceptable salt or derivative thereof and amikacin, and mixtures thereof. In a further embodiment, the composition is administered before, concurrently, or after administration of bedaquiline or a pharmaceutically acceptable salt or derivative thereof.

[0059] In another embodiment, a pharmaceutical combination according to any of the combination embodiments described herein is provided for use in the treatment and / or prevention of pulmonary infections caused by mycobacteria or other Gram-positive bacteria. In a further embodiment, the infection is caused by a Mycobacterium species selected from nontuberculous mycobacteria and the Mycobacterium tuberculosis complex, and combinations thereof. In a further embodiment, the nontuberculous mycobacteria is selected from Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium abscessus, and Mycobacterium leprae, and combinations thereof. In another embodiment, the infection is an opportunistic infection selected from MAC pulmonary disease and non-tuberculous infections in patients with cystic fibrosis, chronic obstructive pulmonary disease, or acquired immune deficiency syndrome. In another embodiment, the infection is an opportunistic non-tuberculous mycobacterial infection in patients with cystic fibrosis. In another embodiment, the combination for said use comprises bedaquiline or a pharmaceutical composition thereof. In another embodiment, the combination for use is used to administer the composition of the present invention before, simultaneously with, or after administration of a drug selected from bedaquiline or a pharmaceutically acceptable salt or derivative thereof, cefoxitin, amikacin, clarithromycin, pyrazinamide, rifampin, moxifloxacin, levofloxacin, and para-aminosalicylate, and mixtures thereof. In another embodiment, the combination for use is used to administer the composition of the present invention before, simultaneously with, or after administration of a drug selected from bedaquiline or a pharmaceutically acceptable salt or derivative thereof, and amikacin, and mixtures thereof. In another embodiment, the combination for use is used to administer the composition of the present invention before, simultaneously, or after administration of bedaquiline or a pharmaceutically acceptable salt or derivative thereof.

[0060] In another embodiment, a system is provided for use in providing antibiotic activity in treating or providing prophylaxis against pulmonary infections caused by mycobacteria or other gram-positive bacteria, the system comprising: 1) (a) an aerosolized pharmaceutical combination comprising a therapeutically effective dose of clofazimine; 2) Dry powder inhalers and wherein the clofazimine is present in the form of a dry powder; The aerosol particles generated by this system have a mass median aerodynamic diameter of 1-5 μm.

[0061] In further embodiments, a pharmaceutical composition according to any one of the composition embodiments described herein is provided for use in the treatment and / or prevention of a pulmonary fungal infection or Clostridium difficile, or a combination thereof. In another embodiment, a pharmaceutical composition according to any one of the composition embodiments described herein is provided for use in the treatment and / or prevention of a pulmonary fungal infection. In further embodiments, the pulmonary fungal infection is Candida albicans or Aspergillus fumigatus, or a combination thereof.

[0062] In further embodiments, a pharmaceutical combination according to any one of the combination embodiments described herein is provided for use in the treatment and / or prevention of a pulmonary fungal infection or Clostridium difficile, or a combination thereof. A pharmaceutical combination according to any one of the combination embodiments described herein is provided for use in the treatment and / or prevention of a pulmonary fungal infection. In further embodiments, the pulmonary fungal infection is Candida albicans or Aspergillus fumigatus, or a combination thereof.

[0063] In another embodiment, there is provided a method for treating or preventing a pulmonary infection in a patient in need thereof, comprising administering by inhalation a composition according to any one of the composition embodiments described herein. In another embodiment, the infection is caused by a Mycobacterium species selected from nontuberculous mycobacteria and the Mycobacterium tuberculosis complex, and combinations thereof. In a further embodiment, the nontuberculous mycobacterium is selected from Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium abscessus, Mycobacterium erythrorhiz ... In a further embodiment, the infection is an opportunistic infection selected from MAC pulmonary disease and non-tuberculous infections in patients with cystic fibrosis, chronic obstructive pulmonary disease, or acquired immunodeficiency syndrome. The infection is an opportunistic nontuberculous mycobacterial infection in patients with cystic fibrosis.

[0064] In a further embodiment, there is provided a method for treating or preventing pulmonary infections caused by mycobacteria or other Gram-positive bacteria in a patient in need thereof, comprising administering by inhalation a composition according to any one of the composition embodiments described herein before, concurrently with, or after administration of an agent selected from bedaquiline or a pharmaceutically acceptable salt or derivative thereof, cefoxitin, amikacin, clarithromycin, pyrazinamide, rifampin, moxifloxacin, levofloxacin, and para-aminosalicylates, and mixtures thereof. In another embodiment, the agent is bedaquiline or amikacin. In a further embodiment, the agent is bedaquiline.

[0065] Particle size and distribution The therapeutic efficacy of aerosolized therapy depends on the deposited dose and its distribution. Aerosol particle size is one of the important variables in defining the deposited dose and distribution of drug aerosols in the lungs.

[0066] In general, inhaled aerosol particles undergo deposition by one of two mechanisms: impaction, which usually predominates for larger aerosol particles, and sedimentation, which predominates for smaller aerosol particles. Impaction occurs when the momentum of an inhaled aerosol particle is sufficiently great that the particle does not follow the airflow and encounters a physiological surface. In contrast, sedimentation occurs primarily in the lower lung when very small aerosol particles traveling with the inhaled airflow encounter a physiological surface as a result of gravitational settling.

[0067] Pulmonary drug delivery can be achieved by inhalation of aerosols through the mouth and throat. Aerosol particles with an aerodynamic diameter greater than about 5 μm typically do not reach the lungs; instead, they tend to impact the back of the throat and may be swallowed and absorbed orally. Aerosol particles with diameters of about 3 to about 5 μm are small enough to reach the upper and middle lung regions (conducting airways) but are too large to reach the alveoli. Smaller aerosol particles, i.e., about 0.5 to about 3 μm, can reach the alveolar region. Aerosol particles with diameters smaller than about 0.5 μm tend to be exhaled during tidal breathing, but can also be deposited in the alveolar region by breath-holding.

[0068] Aerosols used in pulmonary drug delivery consist of a wide range of aerosol particle sizes, and therefore statistical descriptors are used. Aerosols used in pulmonary drug delivery are usually 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. For particles with uniform density, the volume median diameter (VMD) can be used interchangeably with the MMD. VMD and MMD are determined by laser diffraction. The width of the distribution is described by the geometric standard deviation (GSD). However, the deposition of aerosol particles in the respiratory tract is more accurately described by the aerodynamic diameter of the particles, and therefore the aerodynamic mass median diameter is usually used. MMAD is determined by inertial impaction or time-of-flight measurements.

[0069] Nevertheless, for purposes of description, the aerosol particle size of the aerosol particles is given as the MMAD as determined by measurement at room temperature with a Next Generation Impactor (NGI) in accordance with the US Pharmacopeial Convention. <601> Aerosols,Nasal Sprays,Metered-D This is disclosed in "Aerosol Inhalers, and Dry Powder Inhalers," Pharmaceutical Forum (2003), Volume 29, pages 1176-1210, and also in "Particle Size Analysis of Aerosols from Medicinal Inhalers," by Jolyon Mitchell and Mark Nage, KONA Powder and Particle Journal (2004), Volume 22, pages 32-65.

[0070] According to the present invention, the aerosol particle size is optimized to maximize clofazimine deposition at the site of infection while maximizing tolerability. Aerosol particle size can be expressed using the mass median aerodynamic diameter (MMAD). Large particles (e.g., MMAD > 5 μm) are too large to traverse the tortuosity of the airways and therefore tend to deposit in the extratracheal and upper respiratory tract. Upper respiratory tract deposition of large particles can result in intolerance (e.g., coughing and bronchospasm). Therefore, according to a preferred embodiment, the MMAD of the aerosol should be less than about 5 μm, preferably between about 1 and 5 μm, and more preferably less than 3 μm (< 3 μm).

[0071] However, guided breathing maneuvers can be used to allow larger particles to pass through the extratracheal and upper airways and deeper into the lungs than during ventilated breathing, which can increase central and lower lung deposition of the aerosol. Guided breathing can be as slow as 100 ml / min. Thus, the preferred MMAD of the aerosol when used with guided breathing can be less than about 10 μm.

[0072] Use in treatment and / or prevention The pharmaceutical compositions and combinations (aerosols, aerosolized formulations) and systems according to the invention are intended for use in the treatment and / or prevention of pulmonary infections caused by mycobacteria or other clofazimine-susceptible bacteria, such as Staphylococcus aureus (including methicillin-resistant and vancomycin-intermediate-resistant strains), Streptococcus pneumoniae, and Enterococcus spp. The pharmaceutical compositions and combinations of the invention may also be used for the treatment and / or prevention of pulmonary fungal infections.

[0073] Administration of clofazimine The daily pulmonary dose (ie, the dose deposited in the lung) of clofazimine administered in accordance with the present invention is about 10-20 mg for M. abscessus infections.

[0074] Depending on the once or twice daily dosing frequency, the daily pulmonary dose may be divided accordingly.

[0075] According to the present invention, clofazimine can be administered once or twice daily to provide a total daily pulmonary dose of about 10-20 mg.

[0076] It will be apparent to those skilled in the art that the above amounts relate to clofazimine free base and that dosages of derivatives and salts must be adjusted accordingly based on the MIC of each compound and strain.

[0077] Thus, in a first aspect of the present invention, clofazimine or a pharmaceutically acceptable salt or derivative thereof of a suitable particle size is mixed with one or more physiologically acceptable pharmacologically inert excipients or a mixture of physiologically acceptable pharmacologically inert excipients of a suitable particle size. A pharmaceutical composition for dry powder inhalation is provided, comprising:

[0078] In a second aspect, there is provided a pharmaceutical composition for dry powder inhalation comprising clofazimine of a suitable particle size and a physiologically acceptable, pharmacologically inert solid carrier, said solid carrier comprising one or more physiologically acceptable, pharmacologically inert excipients or a mixture of physiologically acceptable, pharmacologically inert excipients of a suitable particle size.

[0079] In a third aspect, there is provided a pharmaceutical composition according to the second aspect, wherein clofazimine is provided in a polymorphic form or form selected from triclinic form FI, monoclinic form FII and orthorhombic form FIII, and mixtures of such forms.

[0080] In a fourth aspect of the present invention there is provided a pharmaceutical composition according to the third aspect, wherein clofazimine is provided substantially in orthorhombic form FIII.

[0081] In a fifth aspect, there is provided a pharmaceutical composition according to any of the first to fourth aspects, wherein the solid carrier is selected from glucose, arabinose, maltose, sucrose, dextrose and lactose, and combinations thereof.

[0082] In a sixth aspect, there is provided a pharmaceutical composition according to any of the first to fifth aspects, wherein the solid carrier is provided in the form of coarse particles having a mass median diameter between 50 and 500 μm.

[0083] In a seventh aspect, there is provided a composition according to any of the first to sixth aspects, wherein the clofazimine is provided in the form of micronised particles having a mass median aerodynamic diameter of less than 5 μm.

[0084] In an eighth aspect, there is provided a composition according to the seventh aspect, wherein the clofazimine is provided in the form of micronised particles having a mass median aerodynamic diameter of between 1 μm and 3 μm.

[0085] In a ninth aspect, there is provided a composition according to any one of the first to fourth aspects, wherein the particles have a uniform composition and the particles comprise both clofazimine and one or more excipients.

[0086] In a tenth aspect, there is provided a composition according to the ninth aspect, wherein the particles have a mass median aerodynamic diameter of less than 5 μm.

[0087] In an eleventh aspect, there is provided a composition according to either the ninth or tenth aspect, wherein the particles have a mass median aerodynamic diameter of between 1 μm and 3 μm.

[0088] In a twelfth aspect, there is provided a composition according to any of the first to eleventh aspects, wherein the excipient comprises a phospholipid or a combination of phospholipids.

[0089] In a thirteenth aspect, there is provided a composition according to any of the first to eleventh aspects, wherein the excipient comprises a salt.

[0090] In a fourteenth aspect, there is provided a composition according to any one of the first to eleventh aspects, wherein the excipient comprises an amino acid or a combination of amino acids.

[0091] In a fifteenth aspect, there is provided a composition according to any one of the first to eleventh aspects, wherein the excipient comprises a sugar or a combination of sugars.

[0092] In a sixteenth aspect, a dry powder inhaler and a dry powder inhaler according to any one of the first to fifteenth aspects are provided. A pharmaceutical combination is provided that includes the dry powder composition and a means for introducing the inhalable dry powder composition into the respiratory tract of a patient by inhalation.

[0093] In a seventeenth aspect, there is provided a pharmaceutical combination according to the sixteenth aspect, wherein the dry powder inhaler is a single dose or multi-dose inhaler.

[0094] In an eighteenth aspect, there is provided a pharmaceutical combination according to the sixteenth aspect, wherein the dry powder inhaler device is pre-metered or device-metered.

[0095] In a nineteenth aspect, there is provided a pharmaceutical composition according to any one of the first to fifteenth aspects for use in the treatment and / or prevention of pulmonary infections caused by mycobacteria or other Gram-positive bacteria.

[0096] In a twentieth aspect, there is provided a pharmaceutical combination according to any of the aspects of claims 16 to 18 for use in the treatment and / or prevention of pulmonary infections caused by mycobacteria or other Gram-positive bacteria.

[0097] In a twenty-first aspect, there is provided a pharmaceutical composition for use according to the nineteenth aspect, wherein the infection is caused by a Mycobacterium species selected from non-tuberculous mycobacteria and the Mycobacterium tuberculosis complex, and combinations thereof.

[0098] In a twenty-second aspect, there is provided a pharmaceutical combination for use according to the twentieth aspect, wherein the infection is caused by a Mycobacterium species selected from non-tuberculous mycobacteria and the Mycobacterium tuberculosis complex, and combinations thereof.

[0099] In a twenty-third aspect, there is provided a pharmaceutical composition according to the twenty-first aspect, wherein the non-tuberculous mycobacterium is selected from Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium abscessus, and Mycobacterium leprae, and combinations thereof.

[0100] In a twenty-fourth aspect, there is provided a pharmaceutical combination for use according to the twenty-second aspect, wherein the non-tuberculous mycobacteria is selected from Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium abscessus, and Mycobacterium leprae, and combinations thereof.

[0101] In a 25th aspect, there is provided a pharmaceutical composition for use according to the 21st aspect, wherein the infection is an opportunistic infection selected from MAC pulmonary disease and non-tuberculous infections in patients with cystic fibrosis, chronic obstructive pulmonary disease or acquired immune deficiency syndrome.

[0102] In a 26th aspect, there is provided a pharmaceutical combination for use according to the 22nd aspect, wherein the infection is an opportunistic infection selected from MAC pulmonary disease and non-tuberculous infections in patients with cystic fibrosis, chronic obstructive pulmonary disease or acquired immune deficiency syndrome.

[0103] In a twenty-seventh aspect, the infection is an opportunistic nontuberculous mycobacterium infection in a patient with cystic fibrosis. There is provided a pharmaceutical composition according to a twenty-fifth aspect for treating an Icobacterial infection.

[0104] In a twenty-eighth aspect, there is provided a pharmaceutical combination according to the twenty-sixth aspect, wherein the infection is an opportunistic non-tuberculous mycobacterial infection in a patient with cystic fibrosis.

[0105] In a twenty-ninth aspect, there is provided a system for use in providing antibiotic activity in treating or providing prophylaxis against pulmonary infections caused by mycobacteria or other gram-positive bacteria, the system comprising: 1) a) a therapeutically effective dose of clofazimine; b) one or more excipients selected from sugars, amino acids, and phospholipids, and combinations thereof a dry powder pharmaceutical formulation comprising: 2) a container for the formulation selected from a capsule or a blister package; 3) Dry powder inhalers and wherein the clofazimine is present in the form of a dry powder and the clofazimine-containing particles have a mass median diameter of 1 to 5 μm.

[0106] In a thirtieth aspect, there is provided a pharmaceutical composition according to any of the nineteenth, twenty-first, twenty-third, twenty-fifth, or twenty-seventh aspects, wherein the composition is administered before, simultaneously with, or after administration of a drug selected from bedaquiline or a pharmaceutically acceptable salt or derivative thereof, cefoxitin, amikacin, clarithromycin, pyrazinamide, rifampin, moxifloxacin, levofloxacin, and para-aminosalicylates, and mixtures thereof.

[0107] In a thirty-first aspect, there is provided a pharmaceutical combination according to any of the twentieth, twenty-second, twenty-fourth, twenty-fifth or twenty-eighth aspects, wherein the pharmaceutical combination is used for administration before, simultaneously with, or after administration of a drug selected from bedaquiline or a pharmaceutically acceptable salt or derivative thereof, cefoxitin, amikacin, clarithromycin, pyrazinamide, rifampin, moxifloxacin, levofloxacin, and para-aminosalicylates, and mixtures thereof.

[0108] In a thirty-second aspect, there is provided a pharmaceutical composition according to the thirtieth aspect, wherein the drug is bedaquiline.

[0109] In a thirty-third aspect, there is provided a pharmaceutical combination according to the thirty-first aspect, wherein the drug is bedaquiline.

[0110] In a thirty-fourth aspect, there is provided a pharmaceutical composition according to the thirtieth aspect, wherein the drug is amikacin.

[0111] In a thirty-fifth aspect, there is provided a pharmaceutical combination according to the thirtieth aspect, wherein the drug is amikacin.

[0112] In a thirty-sixth aspect, there is provided a method for treating or preventing a pulmonary infection caused by mycobacteria or other Gram-positive bacteria in a patient in need thereof, comprising administering by inhalation a composition according to any one of the first to fifteenth aspects.

[0113] In a 37th aspect, there is provided a method of treatment or prevention according to the 36th aspect, wherein the infection is caused by a Mycobacterium species selected from non-tuberculous mycobacteria and the Mycobacterium tuberculosis complex, and combinations thereof.

[0114] In a thirty-eighth aspect, there is provided a method of treatment or prevention according to the thirty-seventh aspect, wherein the non-tuberculous mycobacterium is selected from Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium abscessus, and Mycobacterium leprae, and combinations thereof.

[0115] In a 39th aspect, there is provided a method of treatment or prevention according to the 36th aspect, wherein the infection is an opportunistic infection selected from MAC pulmonary disease and non-tuberculous infections in patients with cystic fibrosis, chronic obstructive pulmonary disease or acquired immune deficiency syndrome.

[0116] In a fortieth aspect, there is provided a method of treatment or prevention according to the thirty ninth aspect, wherein the infection is an opportunistic non-tuberculous mycobacterial infection in a patient with cystic fibrosis.

[0117] In a forty-first aspect, there is provided a method for treating or preventing pulmonary infections caused by mycobacteria or other gram-positive bacteria in a patient in need thereof, comprising administering by inhalation a composition according to any one of the first to fifteenth aspects, before, simultaneously with, or after administration of a drug selected from bedaquiline or a pharmaceutically acceptable salt or derivative thereof, cefoxitin, amikacin, clarithromycin, pyrazinamide, rifampin, moxifloxacin, levofloxacin, and para-aminosalicylates, and mixtures thereof.

[0118] In a 42nd aspect, there is provided a method of treatment or prevention according to the 41st aspect, wherein the agent is bedaquiline or amikacin.

[0119] In a 43rd aspect, there is provided a method of treatment or prevention according to the 42nd aspect, wherein the agent is bedaquiline. [Example]

[0120] Example 1: Aerolizer DPI One embodiment of the present invention uses an Aerolizer DPI, an inhaler in which the drug is stored in a capsule. Clofazimine is micronized by jet mill to particles with an MMD of less than 2 μm and then blended with larger lactose particles (MMD greater than 50 μm) to form a formulation. The formulation is approximately 30% clofazimine by weight. Approximately 250 mg of the formulation (75 mg clofazimine) is filled into a capsule. Since 13% to 28% of the dose is deposited in the lungs, this embodiment delivers between 9.75 mg and 21 mg of clofazimine to the lungs.

Claims

1. A pharmaceutical composition for dry powder inhalation comprising clofazimine or a pharmaceutically acceptable salt or derivative thereof of an appropriate particle size and one or more physiologically acceptable, pharmacologically inert excipients or a mixture of physiologically acceptable, pharmacologically inert excipients of an appropriate particle size.

2. A pharmaceutical composition for dry powder inhalation comprising clofazimine of an appropriate particle size and a physiologically acceptable, pharmacologically inert solid carrier, said solid carrier comprising one or more physiologically acceptable, pharmacologically inert excipients or a mixture of physiologically acceptable, pharmacologically inert excipients of an appropriate particle size.

3. 3. The pharmaceutical composition of claim 2, wherein the clofazimine is provided in a polymorphic form or a form selected from triclinic form FI, monoclinic form FII and orthorhombic form FIII, and mixtures of such forms.

4. 4. The pharmaceutical composition of claim 3, wherein the clofazimine is provided substantially in orthorhombic form FIII.

5. The composition of any one of claims 1 to 4, wherein the solid carrier is selected from glucose, arabinose, maltose, sucrose, dextrose and lactose, and combinations thereof.

6. The composition according to any one of claims 1 to 5, wherein the solid carrier is provided in the form of coarse particles having a mass median diameter between 50 and 500 µm.

7. A composition according to any one of claims 1 to 6, wherein the clofazimine is provided in the form of micronised particles having a mass median aerodynamic diameter of less than 5 μm.

8. 8. The composition of claim 7, wherein the clofazimine is provided in the form of micronized particles having a mass median aerodynamic diameter of between 1 μm and 3 μm.

9. 5. The composition of any one of claims 1 to 4, wherein the particles have a uniform composition and comprise both clofazimine and one or more excipients.

10. 10. The composition of claim 9, wherein the particles have a mass median aerodynamic diameter of less than 5 μm.

11. 11. The composition of claim 9 or 10, wherein the particles have a mass median aerodynamic diameter between 1 μm and 3 μm.

12. The composition of any one of claims 1 to 11, wherein the excipient comprises a phospholipid or a combination of phospholipids.

13. The composition of any one of claims 1 to 11, wherein the excipient comprises a salt.

14. The composition of any one of claims 1 to 11, wherein the excipient comprises an amino acid or a combination of amino acids.

15. The composition of any one of claims 1 to 11, wherein the excipient comprises a sugar or a combination of sugars.

16. A pharmaceutical combination comprising a dry powder inhaler device, a dry powder composition according to any one of claims 1 to 15, and means for introducing the inhalable dry powder composition into the respiratory tract of a patient by inhalation.

17. 17. The pharmaceutical combination of claim 16, wherein the dry powder inhaler is a single dose or multi-dose inhaler.

18. 17. The pharmaceutical combination of claim 16, wherein the dry powder inhaler device is a pre-metered or device-metered device.

19. A pharmaceutical composition according to any one of claims 1 to 15 for use in the treatment and / or prevention of pulmonary infections caused by mycobacteria or other gram-positive bacteria.

20. A pharmaceutical combination according to any one of claims 16 to 18 for use in the treatment and / or prevention of pulmonary infections caused by mycobacteria or other gram-positive bacteria.

21. 20. The pharmaceutical composition for use according to claim 19, wherein the infection is caused by a Mycobacterium species selected from non-tuberculous mycobacteria and Mycobacterium tuberculosis complex, and combinations thereof.

22. 21. The pharmaceutical combination for use according to claim 20, wherein the infection is caused by a Mycobacterium species selected from non-tuberculous mycobacteria and Mycobacterium tuberculosis complex, and combinations thereof.

23. 22. The pharmaceutical composition of claim 21, wherein the nontuberculous mycobacteria is selected from Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium abscessus, and Mycobacterium leprae, and combinations thereof.

24. 23. The pharmaceutical combination for use according to claim 22, wherein the non-tuberculous mycobacteria is selected from Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium abscessus, and Mycobacterium leprae, and combinations thereof.

25. 22. The pharmaceutical composition for use according to claim 21, wherein the infection is an opportunistic infection selected from MAC lung disease and non-tuberculous infections in patients with cystic fibrosis, chronic obstructive pulmonary disease or acquired immune deficiency syndrome.

26. 23. The pharmaceutical combination for use according to claim 22, wherein the infection is an opportunistic infection selected from MAC lung disease and non-tuberculous infections in patients with cystic fibrosis, chronic obstructive pulmonary disease or acquired immune deficiency syndrome.

27. 26. The pharmaceutical composition of claim 25, wherein the infection is an opportunistic nontuberculous mycobacterial infection in a patient with cystic fibrosis.

28. 27. The pharmaceutical combination of claim 26, wherein the infection is an opportunistic nontuberculous mycobacterial infection in a patient with cystic fibrosis.

29. 1. A system for use in providing antibiotic activity in treating or providing prophylaxis against pulmonary infections caused by mycobacteria or other gram-positive bacteria, comprising: 1) a) a therapeutically effective dose of clofazimine; b) one or more excipients selected from sugars, amino acids, and phospholipids, and combinations thereof a dry powder pharmaceutical formulation comprising: 2) a container for the formulation selected from a capsule or a blister package; 3) Dry powder inhalers and wherein the clofazimine is present in the form of a dry powder and the clofazimine-containing particles have a mass median diameter of 1 to 5 μm.

30. 28. The pharmaceutical composition of any one of claims 19, 21, 23, 25 or 27, wherein the composition is administered before, simultaneously with, or after administration of a drug selected from bedaquiline or a pharmaceutically acceptable salt or derivative thereof, cefoxitin, amikacin, clarithromycin, pyrazinamide, rifampin, moxifloxacin, levofloxacin, and para-aminosalicylates, and mixtures thereof.

31. 29. The pharmaceutical combination of any one of claims 20, 22, 24, 25 or 28, wherein the pharmaceutical combination is used for administration before, simultaneously with, or after administration of a drug selected from bedaquiline or a pharmaceutically acceptable salt or derivative thereof, cefoxitin, amikacin, clarithromycin, pyrazinamide, rifampin, moxifloxacin, levofloxacin, and para-aminosalicylates, and mixtures thereof.

32. 31. The pharmaceutical composition of claim 30, wherein the drug is bedaquiline.

33. 32. The pharmaceutical combination of claim 31, wherein the drug is bedaquiline.

34. 31. The pharmaceutical composition of claim 30, wherein the drug is amikacin.

35. 32. The pharmaceutical combination of claim 31, wherein the agent is amikacin.

36. 16. A method for the treatment or prevention of pulmonary infections caused by mycobacteria or other gram-positive bacteria in a patient in need thereof, comprising administering by inhalation a composition according to any one of claims 1 to 15.

37. 37. A method of treatment or prevention according to claim 36, wherein the infection is caused by a Mycobacterium species selected from non-tuberculous mycobacteria and Mycobacterium tuberculosis complex, and combinations thereof.

38. The nontuberculous mycobacterium is selected from Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium abscessus, and Mycobacterium leprae, and combinations thereof.

38. The method of treatment or prevention according to claim 37,

39. 37. The method of treatment or prevention according to claim 36, wherein the infection is an opportunistic infection selected from MAC lung disease and non-tuberculous infections in patients with cystic fibrosis, chronic obstructive pulmonary disease or acquired immune deficiency syndrome.

40. 40. The method of treatment or prevention according to claim 39, wherein the infection is an opportunistic nontuberculous mycobacterial infection in a patient with cystic fibrosis.

41. 16. A method for the treatment or prevention of pulmonary infections caused by mycobacteria or other gram-positive bacteria in a patient in need thereof, comprising administering by inhalation the composition of any one of claims 1 to 15 before, simultaneously with, or after administration of a drug selected from bedaquiline or a pharmaceutically acceptable salt or derivative thereof, cefoxitin, amikacin, clarithromycin, pyrazinamide, rifampin, moxifloxacin, levofloxacin, and para-aminosalicylates, and mixtures thereof.

42. 42. The method of treatment or prevention according to claim 41, wherein the drug is bedaquiline or amikacin.

43. 43. The method of treatment or prevention according to claim 42, wherein the drug is bedaquiline.

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