Methods for treating pulmonary non-tuberculous mycobacterial infections

Abstract

To provide methods for treating a pulmonary infection in a patient in need thereof, for example, a nontuberculous mycobacterial pulmonary infection for at least one treatment cycle.SOLUTION: The method comprises administering to the lungs of the patient a pharmaceutical composition comprising a liposomal complexed aminoglycoside comprising a lipid component comprising electrically neutral lipids and an aminoglycoside. Administration comprises aerosolizing the pharmaceutical composition to provide an aerosolized pharmaceutical composition comprising a mixture of free aminoglycoside and liposomal complexed aminoglycoside, and administering the aerosolized pharmaceutical composition via a nebulizer to the lungs of the patient. The method provided herein results in a change from the baseline on the semi-quantitative scale for mycobacterial culture for a treated patient, and / or NTM culture conversion to negative during or after the administration period.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority from U.S. Provisional Application Nos. 61 / 993,439, filed May 15, 2014; 62 / 042,126, filed August 26, 2014; 62 / 048,068, filed September 9, 2014; and 62 / 056,296, filed September 26, 2014, the disclosures of each of which are incorporated by reference in their entirety for all purposes. [Background technology]

[0002]

[0002] Certain technologies suitable for administration by inhalation use liposomes, lipid complexes that provide a prolonged therapeutic effect of drugs in the lungs. These technologies also provide drugs with sustained activity and the ability to target and promote drug uptake to disease sites.

[0003]

[0003] Inhalation delivery of liposomes is complicated by their sensitivity to shear-induced stress during nebulization, which can alter physical characteristics (e.g., entrapment, size). However, as long as the changes in characteristics are reproducible and meet acceptability criteria, they need not be prohibitive for pharmaceutical development.

[0004]

[0004] Pulmonary infections due to nontuberculous mycobacteria (NTM) in susceptible hosts can result in potentially severe morbidity and even mortality among infected individuals. Due to rising infection rates, nontuberculous mycobacterial pulmonary disease (PNTM) represents an emerging public health concern in the United States. NTM are ubiquitous in the environment. More than 80% of NTM pulmonary (PNTM) infections in the United States are caused by Mycobacterium avium complex (MAC). Additionally, M. kansasii, M. abscessus, and M. fortuitum are commonly isolated.

[0005]

[0005] The prevalence of NTM lung infections in the United States has more than doubled in the last 15 years. The ATS / IDSA PNTM reported a 2-year prevalence of NTM lung infections of 8.6 / 100,000. The prevalence of NTM lung infections increases with age, reaching 20.4 / 100,000 in people at least 50 years of age, and is particularly prevalent in women (median age: 66 years; women: 59%).

[0006]

[0006] In susceptible individuals, NTM pulmonary infections can be severe or life-threatening. Available treatments can be poorly tolerated and can have significant adverse events. The present invention addresses this and other needs by providing a method for treating NTM pulmonary infections in patients in need thereof. Summary of the Invention [Means for solving the problem]

[0007] In one aspect, the present invention provides a method for treating or providing prophylaxis against nontuberculous mycobacterial (NTM) infection (a pulmonary infection caused by or due to one or more nontuberculous mycobacteria) via inhalation administration to a patient in need thereof of an effective amount of a composition comprising a liposome-complexed aminoglycoside or a pharmaceutically acceptable salt thereof. In one embodiment, the patient in need of treatment is a cystic fibrosis patient, a bronchiectasis patient, has asthma, or has chronic obstructive pulmonary disease (COPD).

[0008]

[0008] In one embodiment, the NTM infection is M. avium, M. avium subsp. M.conspicuum, M.kansasii, M.peregrinum, M.immunogenum, M.xenopi, M.marinum, M.malmoense, M.marinum, M.mucogenicum, M.nonchromogenicum, M.scrofulaceum, M.simiae, M.smegmatis, M.szulgai, M.terrae, M.terrae complex, M.haemophilum, M.genavense, M.gordonae, M.ulcerans, M.fortuitum, M.fortuitum complex(M. In one embodiment, the NTM infection is a refractory NTM lung infection. In another ...

[0009] In one embodiment, the composition comprising the liposome-complexed aminoglycoside is a dispersion (e.g., a liposomal solution or suspension). The liposome portion of the composition comprises a lipid component comprising an electrically neutral lipid. In a further embodiment, the electrically neutral lipid comprises phosphatidylcholine and a sterol (e.g., dipalmitoylphosphatidylcholine and cholesterol). In a further embodiment, the aminoglycoside is amikacin or a pharmaceutically acceptable salt thereof. In yet a further embodiment, the aminoglycoside is amikacin sulfate.

[0010]

[0010] In one embodiment, a method for treating or providing prophylaxis against an NTM infection comprises administering an aerosolized pharmaceutical composition to the lungs of a patient in need thereof, wherein the aerosolized pharmaceutical composition comprises a mixture of a free aminoglycoside and a liposome-complexed aminoglycoside, and the lipid component of the liposome is composed of an electrically neutral lipid. In a further embodiment, the electrically neutral lipid comprises phosphatidylcholine and a sterol (e.g., dipalmitoylphosphatidylcholine and cholesterol). In a further embodiment, the aminoglycoside is amikacin or a pharmaceutically acceptable salt thereof. In yet a further embodiment, the aminoglycoside is amikacin sulfate.

[0011] The methods provided herein result in a change from baseline in a semi-quantitative measure of mycobacterial cultures and / or a negative conversion of NTM cultures for treated patients during or after the administration period. For example, in one embodiment, the methods provided herein result in patients having a negative conversion of NTM cultures after the administration period.

[0012] In one embodiment, the aminoglycoside or a pharmaceutically acceptable salt thereof is amikacin, apramycin, arbekacin, astromycin, capreomycin, dibekacin, framycetin, gentamicin, hygromycin B, isepamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodestreptomycin, ribostamycin, sisomicin, spectinomycin, streptomycin, tobramycin, verdamycin, a pharmaceutically acceptable salt thereof, or a combination thereof. In yet a further embodiment, the aminoglycoside is amikacin. In another embodiment, the aminoglycoside is selected from the aminoglycosides, pharmaceutically acceptable salts thereof, or combinations thereof set forth in Table 1 below.

[0013] [Table 1]

[0014] In one embodiment, the pharmaceutical composition provided herein is a liposomal dispersion (i.e., a liposomal dispersion or aqueous liposomal dispersion, which can be either a liposomal solution or a liposomal suspension). In one embodiment, the lipid component of the liposome consists essentially of one or more electrically neutral lipids. In a further embodiment, the electrically neutral lipid comprises a phospholipid and a sterol. In a further embodiment, the phospholipid is dipalmitoylphosphatidylcholine (DPPC) and the sterol is cholesterol.

[0015] In one embodiment, the weight ratio of lipid to aminoglycoside in the aminoglycoside pharmaceutical composition (aminoglycoside liposome solution or suspension) is about 2:1, about 2:1 or less, about 1:1, about 1:1 or less, about 0.75:1 or less, or about 0.7:1. In another embodiment, the weight ratio of lipid to aminoglycoside in the composition is about 0.10:1 to about 1.25:1, about 0.10:1 to about 1.0:1, about 0.25:1 to about 1.25:1, or about 0.5:1 to about 1:1.

[0016] In one embodiment, the method provided herein involves administering a liposomal aminoglycoside composition via nebulization or aerosolization. Accordingly, the method in this embodiment involves generating an aerosolized aminoglycoside composition. In one embodiment, upon nebulization, the aerosolized composition has an aerosol droplet size of about 1 μm to about 3.8 μm, about 1.0 μm to 4.8 μm, about 3.8 μm to about 4.8 μm, or about 4.0 μm to about 4.5 μm. In a further embodiment, the aminoglycoside is amikacin. In yet a further embodiment, the amikacin is amikacin sulfate.

[0017] In one embodiment, about 70% to about 100% of the aminoglycoside present in the composition is liposome-complexed, e.g., encapsulated in multiple liposomes, prior to administration to a patient in need of treatment. In a further embodiment, the aminoglycoside is selected from the aminoglycosides provided in Table 1. In a further embodiment, the aminoglycoside is amikacin (e.g., as amikacin sulfate). In yet a further embodiment, about 80% to about 100% of the amikacin is liposome-complexed, or about 80% to about 100% of the amikacin is encapsulated in multiple liposomes, prior to administration to a patient in need of treatment. In another embodiment, about 80% to about 100%, about 80% to about 99%, about 90% to about 100%, 90% to about 99%, or about 95% to about 99% of the aminoglycoside present in the composition is liposome-complexed prior to administration to a patient in need of treatment (i.e., prior to nebulization).

[0018] In one embodiment, the percent of aminoglycoside complexed with liposomes (also referred to herein as "liposome-associated") after nebulization is about 50% to about 80%, about 50% to about 75%, about 50% to about 70%, about 55% to about 75%, or about 60% to about 70%. In a further embodiment, the aminoglycoside is selected from the aminoglycosides provided in Table 1. In a further embodiment, the aminoglycoside is amikacin. In yet a further embodiment, the amikacin is amikacin sulfate. In one embodiment, the aerosolized (i.e., post-nebulization) composition comprises about 65% to about 75% liposome-complexed aminoglycoside and about 25% to about 35% free aminoglycoside. In a further embodiment, the aminoglycoside is amikacin. In yet a further embodiment, the amikacin is amikacin sulfate.

[0019] In one embodiment, the pulmonary infection treated by the methods provided herein is a Mycobacterium abscessus pulmonary infection or a Mycobacterium avium complex pulmonary infection. In one or more of the foregoing embodiments, the patient is a cystic fibrosis patient, a bronchiectasis patient, an asthma patient, or a COPD patient.

[0020] In one embodiment, a patient with cystic fibrosis is treated for a pulmonary infection with one of the compositions or systems provided herein. In a further embodiment, the pulmonary infection is caused by Mycobacterium abscessus or Mycobacterium avium complex.

[0021] In one embodiment, the concentration of the aminoglycoside in the liposomal aminoglycoside composition is about 50 mg / mL or greater. In a further embodiment, the concentration of the aminoglycoside in the liposomal complexed aminoglycoside is about 60 mg / mL or greater. In a further embodiment, the concentration of the aminoglycoside in the liposomal complexed aminoglycoside is about 70 mg / mL or greater, e.g., about 70 mg / mL to about 75 mg / mL. In a further embodiment, the aminoglycoside is selected from the aminoglycosides provided in Table 1. In yet a further embodiment, the aminoglycoside is amikacin (e.g., amikacin sulfate). [Brief explanation of the drawings]

[0022] [Figure 1] FIG. 1 shows the study design for a randomized, double-blind, placebo-controlled study of liposome-complexed amikacin in patients with refractory nontuberculous mycobacterial (NTM) pulmonary infections, as described in Example 1. [Figure 2] FIG. 1 shows the patient distribution for a randomized, double-blind, placebo-controlled study of liposome-complexed amikacin in patients with refractory nontuberculous mycobacterial pulmonary infections, as described in Example 1. [Figure 3]

[0023] Graph showing the number of patients in each NTM treatment group. [Figure 4]

[0024] FIG. 1 is a graph showing the mean change from baseline on a logarithmic scale (LS) of the complete semi-quantitative measure of mycobacterial cultures as a function of study day for the modified intent to treat patient (mITT) population for both the double-blind and open-label phases of the study shown in Example 1. [Figure 5]

[0025] Figure 5 (top) is a bar graph showing the proportion of patients with NTM cultures converting negatively at various time points during a randomized, double-blind, placebo-controlled trial (modified intention-to-treat population). Figure 5 (bottom) is a bar graph showing the proportion of MAC patients with NTM cultures converting negatively at various time points. [Figure 6]

[0026] 1 is a table showing patients with at least one NTM culture-negative result at various time points during the randomized, double-blind, placebo-controlled study. [Figure 7]

[0027] Figure 7 (top panel) is a graph showing the change from baseline in the 6-minute walk test on days 84 and 168 (mITT population), and Figure 7 (bottom panel) is a graph of the mean change from baseline in distance walked (meters) in the 6MWT for patients receiving LAI versus placebo on day 84 (last observation carried forward, modified intention-to-treat population). [Figure 8]

[0028] Figure 8 (top panel) is a graph showing the mean meters walked in the 6-minute walk test on days 84 and 168 (all patients). Figure 8 (bottom panel) is a graph showing the mean change from baseline to days 84 and 168 in distance walked (meters) in the 6MWT for patients with culture conversion (three or more negative cultures) versus patients without culture conversion (last observation carried forward, modified intention-to-treat population). [Figure 9]

[0029] FIG. 1 shows the study design for a randomized, placebo-controlled trial of liposome-encapsulated amikacin (ARIKAYCE or LAI) in patients with non-cystic fibrosis (non-CF) M. avium complex (MAC) pulmonary infection, as described in Example 2. DETAILED DESCRIPTION OF THE INVENTION

[0023]

[0030] The invention described herein is directed, in part, to a method for treating a pulmonary infection in a patient in need thereof, e.g., administering an aminoglycoside pharmaceutical composition to the patient's lungs, e.g., via nebulization.

[0024]

[0031] As used herein, the term "about" refers to plus or minus 10 percent of the object that it modifies.

[0025]

[0032] The term "treating" includes: (1) preventing or delaying the onset of clinical symptoms of a condition, disorder, or condition in a subject who may be afflicted with or predisposed to the condition, disorder, or condition, but who has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder, or condition; (2) arresting the condition, disorder, or condition (i.e., halting, reducing, or delaying the onset of the disease or, in the case of maintenance therapy, the recurrence of at least one clinical or subclinical symptom thereof); and / or (3) alleviating the condition (i.e., causing regression of the condition, disorder, or condition, or at least one of its clinical or subclinical symptoms). The benefit to a treated subject is statistically significant or at least perceptible to the subject or the physician.

[0026]

[0033] As used herein, "prevention" can mean preventing an infection or disease altogether, or preventing the onset of symptoms of said infection or disease; delaying the onset of an infection or disease or its symptoms; or reducing the severity of an infection or disease or its symptoms that subsequently occurs.

[0027]

[0034] The term "antibacterial" is art-recognized and refers to the ability of the compounds of the present invention to prevent, inhibit, or destroy the growth of bacterial microorganisms, examples of which are provided above.

[0028]

[0035] The term "antimicrobial" is art-recognized and refers to the ability of the aminoglycoside compounds of the present invention to prevent, inhibit, retard or destroy the growth of microorganisms such as bacteria, fungi, protozoa and viruses.

[0029]

[0036] "Effective amount" refers to the amount of aminoglycoside (e.g., amikacin) used in the present invention sufficient to result in the desired therapeutic response. Effective amounts of the compositions provided herein include both free and liposome-complexed aminoglycosides. For example, in one embodiment, the liposome-complexed aminoglycoside includes an aminoglycoside encapsulated in or complexed with a liposome, or a combination thereof.

[0030]

[0037] A "liposome dispersion" refers to a solution or suspension containing a plurality of liposomes.

[0031]

[0038] As used herein, an "aerosol" is a gaseous suspension of liquid particles. The aerosols provided herein include particles of a liposomal dispersion.

[0032]

[0039] A "nebulizer" or "aerosol generator" is a device that converts a liquid into an aerosol of a size that can be inhaled into the respiratory tract. Pneumonic, ultrasonic, and electronic nebulizers, such as passive mesh nebulizers, active mesh nebulizers, and vibrating mesh nebulizers, are suitable for use with the present invention, provided that the particular nebulizer emits an aerosol with the required properties at the required output rate.

[0033]

[0040] The process of converting bulk liquid into small droplets using air pressure is called atomization. The operation of a pneumatic nebulizer requires a supply of pressurized gas as the driving force for liquid atomization. Ultrasonic nebulizers use electrical power introduced by a piezoelectric element in a liquid reservoir to convert liquid into respirable droplets. Various types of nebulizers are described in Respiratory Care, Vol. 45, No. 6, pp. 609-622 (2000), the entire disclosure of which is incorporated herein by reference. The terms "nebulizer" and "aerosol generator" are used interchangeably throughout the specification. The terms "inhalation device," "inhalation system," and "atomizer" are also used interchangeably in the literature, along with the terms "nebulizer" and "aerosol generator."

[0034]

[0041] "Mass Median Diameter" or "MMD" is the average particle size by mass as determined by laser diffraction or impactor measurements.

[0035]

[0042] "Mass median aerodynamic diameter" or "MMAD" is normalized with respect to the aerodynamic separation of aqueous aerosol droplets and is determined by impactor measurements, e.g., an Andersen Cascade Impactor (ACI) or a Next Generation Impactor (NGI). In one embodiment, the gas flow rate is 28 liters per minute with an Andersen Cascade Impactor (ACI) and 15 liters per minute with a Next Generation Impactor (NGI). "Geometric standard deviation" or "GSD" is a measure of the width of the aerodynamic particle size distribution.

[0036]

[0043] Nontuberculous mycobacteria are organisms found in soil and water that can cause severe lung disease in susceptible individuals. Currently, effective treatments for these organisms are limited and there are no approved cures. The prevalence of NTM disease is reported to be increasing and, according to the American Thoracic Society, is believed to be higher than the prevalence of tuberculosis in the United States. According to the National Center for Biotechnology Information, epidemiological studies have shown that the presence of NTM infections is increasing in developing countries, likely due to the introduction of public water supplies. Women with distinctive phenotypes, along with patients with cystic fibrosis transmembrane conductance regulator (CFTR) defects, are considered at higher risk for acquiring NTM infection. In general, high-risk groups for increased morbidity and mortality with NTM lung disease include those with cavitary lesions, a low BMI, older age, and a high comorbidity index.

[0037]

[0044] NTM lung disease is often a chronic condition that can lead to progressive inflammation and lung damage and is characterized by bronchiectasis and cavitary disease. NTM infections often require prolonged hospitalization for medical management. Treatment typically involves multidrug regimens that may be poorly tolerated and have limited effectiveness, especially in patients with severe disease or who have failed previous treatment attempts. According to a company-sponsored patient chart study conducted by Clarity Pharma Research, approximately 50,000 patients with NTM lung disease visited physicians in the United States during 2011.

[0038]

[0045] Management of pulmonary disease caused by nontuberculous mycobacteria (NTM) infection involves prolonged multidrug regimens, which are often associated with drug toxicity and suboptimal outcomes. Achieving negative NTM cultures is one of the goals of treatment and represents the most clinically important microbiological endpoint in patients with NTM pulmonary infections.

[0039]

[0046] In one aspect, the present invention provides a method for treating a nontuberculous mycobacterial (NTM) pulmonary infection in a patient in need thereof. In one embodiment, the method comprises administering to the patient a composition comprising a liposome-complexed aminoglycoside or a pharmaceutically acceptable salt thereof for an administration period. In one embodiment, the liposome-complexed aminoglycoside comprises an aminoglycoside or a pharmaceutically acceptable salt thereof encapsulated in a plurality of liposomes. In one embodiment, the plurality of liposomes comprises a lipid component consisting of a neutral lipid. In one embodiment, the neutral lipid comprises a phospholipid and a sterol. In a further embodiment, the phospholipid is phosphatidylcholine. In yet a further embodiment, the phosphatidylcholine is dipalmitoylphosphatidylcholine (DPPC). In yet a further embodiment, the sterol is cholesterol. In one embodiment, the nontuberculous mycobacterial pulmonary infection is a refractory nontuberculous mycobacterial pulmonary infection. In one embodiment, the patient exhibits an increase in meters walked on the 6MWT compared to pre-treatment and / or negative conversion of NTM cultures during or after the administration period.

[0040]

[0047] Therapeutic response can be any response that a user (e.g., a clinician) recognizes as an effective response to treatment. Therapeutic response is generally a reduction, inhibition, delay, or prevention of the growth or proliferation of one or more NTM, or the death of one or more NTM. Therapeutic response can also be reflected in an improvement in pulmonary function, for example, forced expiratory volume in one second (FEV1). In one embodiment in which a patient is treated for NTM pulmonary infection, the therapeutic response is measured as a change from baseline in a semi-quantitative measure of completeness of mycobacterial culture or an improvement in walking distance in a 6-minute walk test (6MWT). Furthermore, it is within the skill of a person skilled in the art to determine the appropriate treatment duration, appropriate dosage, and any possible combination therapy based on the evaluation of the therapeutic response.

[0041]

[0048] NTM pulmonary infections treatable by the methods and compositions described herein include, in one embodiment, M. avium, M. avium subsp. hominissuis (MAH), M. abscessus, M. chelonae, M. bolletii, M. kansasii, M. ulcerans, M. avium, M. avium complex (MAC) (M. avium and M. intracellulare), M. conpicuum, M. kansasii, M. peregrinum, M. immunogenum, M. xenopi, M. marinum, M. malmoense, M. marinum, M. mucogenicum, M. nonchromogenicum, M. scrofulaceum, M. simiae, M. smegmatis, M. szulgai, M. terrae, and M. terrae. complex, M. haemophilum, M. genavense, M. asiaticum, M. shimoidei, M. gordonae, M. nonchromogenicum, M. triplex, M. lentiflavum, M. celatum, M. fortuitum, M. fortuitum complex (M. fortuitum and M. chelonae), or a combination thereof. In a further embodiment, the nontuberculous mycobacterial pulmonary infection is M. avium complex (MAC) (M. avium and M. intracellulare), M. abscessus, or M. avium. In a further embodiment, the M. avium infection is M. avium subsp. hominissuis. In one embodiment, the nontuberculous mycobacterial pulmonary infection is M. avium complex (MAC) (M. avium and M. intracellulare). In another embodiment, the NTM pulmonary infection is a refractory nontuberculous mycobacterial pulmonary infection.

[0042]

[0049] As described throughout, the compositions and systems described herein are used to treat infections caused by nontuberculous mycobacteria (NTM). In one embodiment, the compositions and systems described herein are used to treat infections caused by Mycobacterium abscessus, Mycobacterium avium, or the M. avium complex. In yet a further embodiment, the Mycobacterium avium infection is Mycobacterium avium subsp. hominissuis.

[0043]

[0050] In one embodiment, a patient is treated for Mycobacterium abscessus, M. kansasii, M. abscessus, M. fortuitum, Mycobacterium avium, or M. avium complex (MAC) pulmonary infection via inhalation delivery of a liposomal aminoglycoside composition. In a further embodiment, the aminoglycoside is amikacin sulfate and is administered once daily in a single dosing session. In yet a further embodiment, the NTM pulmonary infection is MAC.

[0044]

[0051] In one embodiment, the NTM lung infection is associated with cavitary foci. In one embodiment, the NTM lung infection is a nodular infection. In a further embodiment, the NTM lung infection is a nodular infection with microcavitary foci.

[0045]

[0052] In one embodiment, the aminoglycoside or pharmaceutically acceptable salt thereof administered via the methods described herein is selected from amikacin, apramycin, arbekacin, astromycin, capreomycin, dibekacin, framycetin, gentamicin, hygromycin B, isepamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodostreptomycin, ribostamycin, sisomicin, spectinomycin, streptomycin, tobramycin, verdamycin, or a pharmaceutically acceptable salt thereof. In a further embodiment, the aminoglycoside is amikacin. In yet a further embodiment, the amikacin is amikacin sulfate. In another embodiment, the aminoglycoside is selected from the aminoglycosides shown in Table 2 below, their pharmaceutically acceptable salts, or a combination thereof. For example, pharmaceutically acceptable salts, such as sulfate salts, of one or more of the aminoglycosides shown in Table 2 can be formulated into liposomal compositions and administered to patients in need of treatment for NTM via pulmonary delivery, for example, by a nebulizer.

[0046] [Table 2]

[0047]

[0053] In one embodiment, the pharmaceutical composition comprises a combination of aminoglycosides or pharmaceutically acceptable salts thereof, e.g., a combination of two or more aminoglycosides or pharmaceutically acceptable salts thereof shown in Table 2. In one embodiment, the composition comprising a liposome-complexed aminoglycoside comprises one to about five aminoglycosides or pharmaceutically acceptable salts thereof. In another embodiment, the composition comprising a liposome-complexed aminoglycoside comprises at least one, at least two, at least three, at least four, at least five, or at least six aminoglycosides shown in Table 2 (or pharmaceutically acceptable salts of said aminoglycosides). In another embodiment, the pharmaceutical composition comprises between one and four aminoglycosides or pharmaceutically acceptable salts thereof. In a further embodiment, the combination comprises amikacin, e.g., as amikacin sulfate.

[0048]

[0054] In one embodiment, the aminoglycoside is an aminoglycoside free base or a salt, solvate, or other non-covalent derivative thereof. In a further embodiment, the aminoglycoside is amikacin. Suitable aminoglycosides for use in the drug compositions of the present invention include pharmaceutically acceptable addition salts and complexes of the drug. Where a compound may have one or more chiral centers, the present invention includes each unique racemic compound and each unique non-racemic compound unless otherwise specified. Where an active agent has an unsaturated carbon-carbon double bond, both cis (Z) and trans (E) isomers are within the scope of the present invention. Where an active agent exists in tautomeric forms, such as keto-enol tautomers, each tautomeric form is intended to be encompassed within the present invention. In one embodiment, amikacin is present in the pharmaceutical composition as amikacin base or an amikacin salt, e.g., amikacin sulfate or amikacin disulfate. In one embodiment, one or more combinations of the above aminoglycosides are used in the compositions, systems, and methods described herein.

[0049]

[0055] In one aspect, the present invention provides a method for treating or providing prophylaxis against NTM pulmonary infections. Treatment is achieved through delivery of a liposomal aminoglycoside composition by inhalation via nebulization of the composition. In one embodiment, the composition comprises an aminoglycoside encapsulated in multiple liposomes, e.g., an aminoglycoside selected from one or more of the aminoglycosides in Tables 1 and / or 2, or a pharmaceutically acceptable salt thereof.

[0050]

[0056] The pharmaceutical compositions provided herein are liposomal dispersions containing a liposomally complexed aminoglycoside, e.g., an aminoglycoside encapsulated in a plurality of liposomes. The pharmaceutical compositions are dispersions containing "liposomally complexed aminoglycosides" or "liposomally encapsulated aminoglycosides." "Liposomally complexed aminoglycosides" includes embodiments in which the aminoglycoside (or combination of aminoglycosides) is encapsulated in a liposome, and includes any form of aminoglycoside composition in which at least about 1% by weight of the aminoglycoside is associated with liposomes, either as part of a complex with a liposome or as a liposome in which the aminoglycoside can be in the aqueous phase, the hydrophobic bilayer phase, or the interfacial head region of the liposomal bilayer.

[0051]

[0057] In one embodiment, the lipid component of the liposome or liposomes comprises an electrically neutral lipid, a positively charged lipid, a negatively charged lipid, or a combination thereof. In another embodiment, the lipid component comprises an electrically neutral lipid. In a further embodiment, the lipid component consists essentially of an electrically neutral lipid. In yet a further embodiment, the electrically neutral lipid comprises a sterol and a phospholipid. In yet a further embodiment, the sterol is cholesterol and the phospholipid is a neutral phosphatidylcholine. In one embodiment, the phosphatidylcholine is dipalmitoylphosphatidylcholine (DPPC).

[0052]

[0058] As defined above, liposome-complexed aminoglycosides include those in which the aminoglycoside or a pharmaceutically acceptable salt thereof is encapsulated in multiple liposomes. Furthermore, liposome-complexed aminoglycosides refer to any composition, solution, or suspension in which at least about 1% by weight of the aminoglycoside is associated with lipids, either as part of a complex with a liposome or as liposomes in which the aminoglycoside can reside in the aqueous phase, the hydrophobic bilayer phase, or the interfacial head region of the liposome bilayer. In one embodiment, prior to nebulization, at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% of the aminoglycoside in the composition is so associated. In one embodiment, association is measured by separation through a filter, in which lipids and lipid-associated drug are retained (i.e., in the retentate) and free drug is in the filtrate.

[0053]

[0059] The method provided herein includes administering to a patient in need thereof a composition comprising an aminoglycoside or a pharmaceutically acceptable salt thereof encapsulated in a plurality of liposomes. One or more lipids may be used to form the plurality of liposomes. In one embodiment, the one or more lipids are synthetic, semi-synthetic, or natural lipids, including phospholipids, tocopherols, sterols, fatty acids, negatively charged lipids, cationic lipids, or combinations thereof. In one embodiment, the lipid component of the plurality of liposomes is composed of electrically neutral lipids. In a further embodiment, the lipid component comprises DPPC and cholesterol.

[0054]

[0060] In one embodiment, at least one phospholipid is present in the plurality of liposomes. In one embodiment, the phospholipid is completely electrically neutral. In one embodiment, the phospholipid is phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE), and phosphatidic acid (PA); soybean counterpart, soybean phosphatidylcholine (SPC); SPG, SPS, SPI, SPE, and SPA; hydrogenated egg and soybean counterparts (e.g., HEPC, HSPC), phospholipids including choline, glycerol, inositol, serine, ethanolamine, and the corresponding phosphatidic acid, formed from ester bonds between fatty acids containing 12-26 carbon atoms at the 2- and 3-positions of glycerol and various head groups at the 1-position of glycerol. The carbon chains of these fatty acids can be saturated or unsaturated, and phospholipids can be formed from fatty acids of various chain lengths and degrees of unsaturation.

[0055]

[0061] In one embodiment, the lipid component of the plurality of liposomes comprises dipalmitoylphosphatidylcholine (DPPC), a major component of natural pulmonary surfactant. In one embodiment, the lipid component of the plurality of liposomes comprises, consists essentially of, or consists of DPPC and cholesterol. In a further embodiment, the DPPC and cholesterol have a molar ratio ranging from about 19:1 to about 1:1, or from about 9:1 to about 1:1, or from about 4:1 to about 1:1, or from about 2:1 to about 1:1, or from about 1.86:1 to about 1:1. In yet a further embodiment, the DPPC and cholesterol have a molar ratio of about 2:1 or about 1:1.

[0056]

[0062] Other examples of lipids for use with the methods and compositions described herein include, but are not limited to, mixed phospholipids such as dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylglycerol (DPPG), distearoylphosphatidylcholine (DSPC), distearoylphosphatidylglycerol (DSPG), dioleoylphosphatidylethanolamine (DOPE), palmitoylstearoylphosphatidylcholine (PSPC), and monoacylated phospholipids, e.g., mono-oleoylphosphatidylethanolamine (MOPE).

[0057]

[0063] In one embodiment, the lipid component of the plurality of liposomes comprises a sterol. In a further embodiment, at least one lipid component comprises, consists essentially of, or consists of a sterol and a phospholipid (e.g., a neutral phosphatidylcholine such as DPPC). Sterols for use in the present invention include, but are not limited to, cholesterol, cholesterol esters including cholesterol hemisuccinate, cholesterol salts including cholesterol hydrogen sulfate and cholesterol sulfate, ergosterol, ergosterol esters including ergosterol hemisuccinate, ergosterol salts including ergosterol hydrogen sulfate and ergosterol sulfate, lanosterol, lanosterol esters including lanosterol hemisuccinate, lanosterol hydrogen sulfate, lanosterol salts including lanosterol sulfate, and tocopherol. Tocopherols may include tocopherol, esters of tocopherol including tocopherol hemisuccinate, salts of tocopherol including tocopherol hydrogen sulfate and tocopherol sulfate. The term "sterol compound" includes sterols, tocopherols, and the like.

[0058]

[0064] In one embodiment, at least one cationic lipid (a lipid having a positive charge) is provided among the lipid components of a plurality of liposomes present in the liposomal aminoglycoside composition described herein for use in a method for treating NTM pulmonary infection in a patient in need thereof. Cationic lipids suitable for use in the present invention include, but are not limited to, ammonium salts of fatty acids, phospholipids, and glycerides. The fatty acids include fatty acids with carbon chain lengths of 12 to 26 carbon atoms that are saturated or unsaturated. Some specific examples include, but are not limited to, myristylamine, palmitylamine, laurylamine and stearylamine, dilauroylethylphosphocholine (DLEP), dimyristoylethylphosphocholine (DMEP), dipalmitoylethylphosphocholine (DPEP) and distearoylethylphosphocholine (DSEP), N-(2,3-di-(9-(Z)-octadecenyloxy)-prop-1-yl-N,N,N-trimethylammonium chloride (DOTMA), 1,2-bis(oleoyloxy)-3-(trimethylammonio)propane (DOTAP), and combinations thereof.

[0059]

[0065] In one embodiment, at least one anionic lipid (negatively charged lipid) is provided in the lipid components of the plurality of liposomes present in the liposomal aminoglycoside composition described herein for use in a method for treating NTM pulmonary infection in a patient in need thereof. Negatively charged lipids that may be used include phosphatidylglycerol (PG), phosphatidic acid (PA), phosphatidylinositol (PI), and phosphatidylserine (PS). Examples include, but are not limited to, DMPG, DPPG, DSPG, DMPA, DPPA, DSPA, DMPI, DPPI, DSPI, DMPS, DPPS, DSPS, and combinations thereof.

[0060]

[0066] Without wishing to be bound by theory, phosphatidylcholines such as DPPC aid in the uptake of aminoglycoside active agents by cells in the lung (e.g., alveolar macrophages) and help retain aminoglycosides in the lungs. Negatively charged lipids such as PG, PA, PS, and PI are thought to play a role in sustaining the active properties of inhalant compositions and transporting the compositions across the lungs for systemic uptake (transcytosis), in addition to reducing particle aggregation. Without wishing to be bound by theory, sterol compounds are thought to affect the release characteristics of the compositions.

[0061]

[0067] Liposomes are completely closed lipid bilayer membranes containing a trapped volume of water. Liposomes can be unilamellar vesicles (with a single membrane bilayer) or multilamellar vesicles (onion-like structures characterized by multiple membrane bilayers, each separated from the next by an aqueous layer), or a combination thereof. The bilayer consists of two lipid monolayers with hydrophobic "tail" regions and hydrophilic "head" regions. The membrane bilayer structure is such that the hydrophobic (non-polar) "tail" of the lipid monolayer faces toward the center of the bilayer, while the hydrophilic "head" faces toward the aqueous phase.

[0062]

[0068] The weight ratio of lipid to aminoglycoside (weight ratio also referred to herein as "lipid:aminoglycoside") in the pharmaceutical compositions provided herein, in one embodiment, is 3:1 or less, 2.5:1.0 or less, 2:1 or less, 1.5:1 or less, 1:1 or less, or 0.75:1 or less. In one embodiment, the lipid:aminoglycoside weight ratio in the compositions provided herein is 0.7:1.0 or about 0.7:1.0 by weight. In another embodiment, the L:D ratio in the liposomes provided herein is 0.75:1 or less (by weight). In one embodiment, the lipid:aminoglycoside weight ratio is about 0.10:1.0 to about 1.25:1.0, about 0.25:1.0 to about 1.25:1.0, about 0.50:1.0 to about 1.25:1.0, or about 0.6:1 to about 1.25:1.0. In another embodiment, the lipid:aminoglycoside weight ratio is about 0.1:1.0 to about 1.0:1.0, or about 0.25:1.0 to about 1.0:1.0, or about 0.5:1 to 1:1.0.

[0063]

[0069] In other embodiments, the lipid to aminoglycoside weight ratio in the compositions provided herein is less than 3:1, less than 2.5:1.0, less than 2.0:1.0, less than 1.5:1.0, or less than 1.0:1.0. In further embodiments, the lipid to aminoglycoside weight ratio is less than or equal to about 0.7:1.0. In yet other embodiments, the lipid to aminoglycoside weight ratio is from about 0.5:1.0 to about 0.8:1.0.

[0064]

[0070] To minimize administration volume and reduce patient dosing frequency, in one embodiment, it is important that liposomal entrapment of the aminoglycoside (e.g., the aminoglycoside amikacin) be highly efficient and that the lipid-to-aminoglycoside weight ratio be as low as possible and / or practical while keeping the liposomes small enough to penetrate the patient's mucous membranes and biological membranes. In one embodiment, the L-aminoglycoside weight ratio in a composition provided herein, i.e., a composition comprising an aminoglycoside encapsulated in multiple liposomes, is 0.7:1.0, about 0.7:1.0, about 0.5:1.0 to about 0.8:1.0, or about 0.6:1.0 to about 0.8:1.0. In a further embodiment, the liposomes provided herein are small enough to effectively penetrate bacterial biological membranes. In yet a further embodiment, the average diameter of the plurality of liposomes measured by light scattering is about 200 nm to about 400 nm, or about 250 nm to about 400 nm, or about 250 nm to about 300 nm, or about 200 nm to about 300 nm. In yet a further embodiment, the average diameter of the plurality of liposomes measured by light scattering is about 260 to about 280 nm.

[0065]

[0071] In one embodiment, the liposome composition described herein is produced by one of the methods set forth in U.S. Patent Application Publication No. 2013 / 0330400 or U.S. Patent No. 7,718,189, each of which is incorporated by reference in its entirety for all purposes. Liposomes can be produced by a variety of methods (see, e.g., Cullis et al. (1987)). In one embodiment, one or more of the methods described in U.S. Patent Application Publication No. 2008 / 0089927 are used herein to produce aminoglycoside-encapsulated lipid compositions (liposomal dispersions). The disclosure of U.S. Patent Application Publication No. 2008 / 0089927 is incorporated by reference in its entirety for all purposes. For example, in one embodiment, at least one lipid and an aminoglycoside are mixed with a coacervate (i.e., a separate liquid phase) to produce a liposome composition. The coacervate can be produced before, during, or after mixing with the lipid. Additionally, the coacervate can be a coacervate of an active agent.

[0066]

[0072] In one embodiment, the liposome dispersion is produced by dissolving one or more lipids in an organic solvent to produce a lipid solution, and the aminoglycoside coacervate is produced by mixing an aqueous solution of the aminoglycoside with the lipid solution. In a further embodiment, the organic solvent is ethanol. In yet a further embodiment, the lipid solution comprises a phospholipid and a sterol, such as DPPC and cholesterol.

[0067]

[0073] In one embodiment, liposomes are prepared by sonication, extrusion, homogenization, swelling, electroformation, inverted emulsion, or reverse phase evaporation. Bangham's method (J. Mol. Biol. (1965)) produces conventional multilamellar vesicles (MLVs). Lenk et al. (U.S. Patent Nos. 4,522,803, 5,030,453, and 5,169,637), Fountain et al. (U.S. Patent No. 4,588,578), and Cullis et al. (U.S. Patent No. 4,975,282) disclose methods for preparing multilamellar liposomes with substantially equal interphase solute distribution in each of their aqueous compartments. Paphadjopoulos et al., U.S. Patent No. 4,235,871, discloses the preparation of oligolamellar liposomes by reverse phase evaporation. Each method is suitable for use with the present invention.

[0068]

[0074] Unilamellar vesicles can be produced from MLVs by several techniques, such as the injection techniques of U.S. Patent Nos. 5,008,050 and 5,059,421. Sonication and homogenization can be used to produce smaller unilamellar vesicles from larger liposomes (see, e.g., Paphadjopoulos et al. (1968); Deamer and Uster (1983); and Chapman et al. (1968)).

[0069]

[0075] The liposome preparation of Bangham et al. (J. Mol. Biol. 13, 1965, pp. 238-252) involves suspending phospholipids in an organic solvent, which is then evaporated to dryness, leaving a phospholipid membrane in the reaction vessel. An appropriate amount of aqueous phase is then added, the mixture is "swelled," and the resulting liposomes, consisting of multilamellar vesicles (MLVs), are dispersed by mechanical means. This preparation provides the basis for the development of small sonicated unilamellar vesicles and large unilamellar vesicles described by Papahadjopoulos et al. (Biochim. Biophys. Acta. 135, 1967, pp. 624-638).

[0070]

[0076] To prepare liposomes for use in the pharmaceutical compositions provided herein, techniques for preparing large unilamellar vesicles (LUVs) can be used, such as reverse phase evaporation, injection method and surfactant dilution.Reviews of these and other methods for preparing liposomes can be found in the textbook Liposomes, edited by Marc Ostro, Marcel Dekker, Inc., New York, 1983, Chapter 1, which is incorporated herein by reference.See also Szoka, Jr. et al. (Ann. Rev. Biophys. Bioeng. 9, 1980, p. 467), which is also incorporated herein by reference in its entirety for all purposes.

[0071]

[0077] Other techniques for making liposomes include those that produce reverse phase evaporation vesicles (REV), U.S. Patent No. 4,235,871. Another class of liposomes that can be used is characterized by having a substantially equal lamellar solute distribution. This class of liposomes is termed stable plurilamellar vesicles (SPLV), as defined in U.S. Patent No. 4,522,803, and includes the single-phase vesicles described in U.S. Patent No. 4,588,578 and the freeze-thawed multilamellar vesicles (FATMLV) described above.

[0072]

[0078] Various sterols and their water-soluble derivatives, such as cholesterol hemisuccinate, have been used to produce liposomes; see, for example, U.S. Patent No. 4,721,612. Mayhew et al., PCT Publication No. WO85 / 00968, described a method for reducing the toxicity of drugs by encapsulating them in liposomes containing alpha-tocopherol and certain derivatives thereof.Various tocopherols and their water-soluble derivatives have also been used to produce liposomes; see, for example, PCT Publication No. 87 / 02219.

[0073]

[0079] In one embodiment, the pharmaceutical composition contains liposomes having an average diameter, prior to nebulization, measured by light scattering, of approximately 0.01 microns to approximately 3.0 microns, e.g., about 0.2 to about 1.0 microns. In one embodiment, the average diameter of the liposomes in the composition is about 200 nm to about 300 nm, about 210 nm to about 290 nm, about 220 nm to about 280 nm, about 230 nm to about 280 nm, about 240 nm to about 280 nm, about 250 nm to about 280 nm, or about 260 nm to about 280 nm. The sustained activity profile of the liposome product can be adjusted by the properties of the lipid membrane and by including other excipients in the composition.

[0074]

[0080] In one embodiment, the methods described herein include administering a liposome-complexed aminoglycoside composition, e.g., a liposome-complexed amikacin (e.g., amikacin sulfate) composition, to a patient in need thereof via inhalation, e.g., via a nebulizer. In one embodiment, the amount of aminoglycoside provided in the composition is about 450 mg, about 500 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, or about 610 mg. In another embodiment, the amount of aminoglycoside provided in the composition is about 500 mg to about 600 mg, or about 500 mg to about 650 mg, or about 525 mg to about 625 mg, or about 550 mg to about 600 mg. In one embodiment, the amount of aminoglycoside administered to a subject is about 560 mg and is provided in 8 mL of the composition. In one embodiment, the amount of aminoglycoside administered to a subject is about 590 mg and is provided in an 8 mL composition. In one embodiment, the amount of aminoglycoside administered to a subject is about 600 mg and is provided in an 8 mL composition. In one embodiment, the aminoglycoside is amikacin, and the amount of amikacin provided in the composition is about 450 mg, about 500 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, or about 610 mg. In another embodiment, the aminoglycoside is amikacin, and the amount of amikacin provided in the composition is about 500 mg to about 650 mg, or about 525 mg to about 625 mg, or about 550 mg to about 600 mg. In one embodiment, the aminoglycoside is amikacin, and the amount of amikacin administered to a subject is about 560 mg and is provided in an 8 mL composition. In one embodiment, the aminoglycoside is amikacin and the amount of amikacin administered to the subject is 590 mg and is provided in an 8 mL composition. In one embodiment, the aminoglycoside is amikacin and the amount of aminoglycoside administered to the subject is about 600 mg and is provided in an 8 mL composition.

[0075]

[0081] In one embodiment, the methods described herein are carried out through the use of a system comprising a liposome-complexed aminoglycoside composition, e.g., a liposome-encapsulated amikacin composition (e.g., amikacin sulfate) and a nebulizer. In one embodiment, the liposomal aminoglycoside composition provided herein comprises about 60 mg / mL of aminoglycoside, about 65 mg / mL of aminoglycoside, about 70 mg / mL of aminoglycoside, about 75 mg / mL of aminoglycoside, about 80 mg / mL of aminoglycoside, about 85 mg / mL of aminoglycoside, or about 90 mg / mL of aminoglycoside. In a further embodiment, the aminoglycoside is amikacin, e.g., as amikacin sulfate.

[0076]

[0082] In one embodiment of the NTM treatment method described herein, the liposomal aminoglycoside composition is administered to a patient in need thereof once daily in a single dosing session. In a further embodiment, the composition is administered as an aerosol via a nebulizer. In another embodiment, the method comprises administering one of the aminoglycoside compositions described herein to a patient in need thereof every other day or every three days. In yet another embodiment, the method comprises administering one of the aminoglycoside compositions described herein to a patient in need thereof twice daily.

[0077]

[0083] The methods provided herein, in one embodiment, comprise administering one of the compositions described herein (e.g., via a nebulizer) to a patient in need thereof for an administration period comprising at least 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In one embodiment, the administration period is followed by a period during which no composition is administered (referred to as an "off-period"), which is then followed by another administration period. In one embodiment, the off-period is about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months.

[0078]

[0084] In one embodiment, the administration period is from about 15 days to about 400 days, e.g., from about 45 days to about 300 days, or from about 45 days to about 270 days, or from about 80 days to about 200 days. In one embodiment, the administration period comprises administering the composition to a patient in need thereof in a single daily dosing session.

[0079]

[0085] In another embodiment, the methods for treating NTM described herein comprise administering a liposome-complexed aminoglycoside composition to a patient in need thereof via a single daily dosing session for an administration period. In further embodiments, the administration period is from about 15 to about 275 days, or from about 20 to about 235 days, or from about 28 to about 150 days. For example, the methods provided herein comprise administering an aminoglycoside composition to a patient in need thereof once daily in a single dosing session for an administration period of from about 15 to about 300 days, or from about 15 to about 250 days, or from about 15 to about 200 days, or from about 15 to about 150 days, or from about 15 to about 125 days, or from about 15 to about 100 days. In another embodiment, the administration period is from about 50 days to about 200 days. During the administration period, in one embodiment, a patient in need thereof is administered the aminoglycoside composition via nebulization, administering about 500 mg to about 1000 mg of aminoglycoside, e.g., about 500 mg to about 700 mg of aminoglycoside (e.g., about 590 mg of aminoglycoside) daily in a single dosing session.

[0080]

[0086] In one embodiment, the administration period is followed by an off-period of about 15 to about 200 days, e.g., about 15 to about 150 days, or about 15 to about 75 days, about 15 to about 35 days, or about 20 to about 35 days, or about 25 to about 75 days, or about 35 to about 75 days, or about 45 to about 75 days. In another embodiment, the off-period is about 28 days or about 56 days. In other embodiments, the off-period is about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 days, while in other embodiments, the off-period is about 56 days.

[0081]

[0087] In one embodiment, a patient in need thereof is administered a liposome-complexed aminoglycoside composition in a treatment cycle including an on-period and an off-period. In a further embodiment, the treatment cycle is performed at least once. In a further embodiment, the treatment cycle is repeated at least twice, for example, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times. In another embodiment, the treatment cycle is repeated at least three times, for example, at least 3, at least 4, at least 5, or at least 6 times.

[0082]

[0088] Various treatment cycles for patients with NTM pulmonary infections are provided below in Table 3. However, in another embodiment, the methods provided herein do not include an off-period, but instead include only on-periods. In a further embodiment, one of the on-periods shown in Table 3 is used in the methods provided herein. In a further embodiment, the patient is administered the liposomal aminoglycoside composition once daily during the on-period in a single dosing session.

[0083] [Table 3-1]

[0084] [Table 3-2]

[0085]

[0089] In one embodiment, the system provided herein comprises about 8 mL of a liposomal amikacin composition and a nebulizer. In one embodiment, the density of the liposomal amikacin composition is about 1.05 grams / mL; in one embodiment, approximately 8.4 grams of the liposomal amikacin composition is present in the composition of the present invention per dose. In a further embodiment, the entire volume of the composition is administered to a subject in need thereof.

[0086]

[0090] In one embodiment, the pharmaceutical composition provided herein comprises at least one aminoglycoside, at least one phospholipid, and a sterol. In a further embodiment, the pharmaceutical composition comprises an aminoglycoside, DPPC, and cholesterol. In one embodiment, the pharmaceutical composition is a composition provided in Table 4 below.

[0087] [Table 4]

[0088]

[0091] It should be noted that increasing the aminoglycoside concentration alone may not result in a reduction in dosing frequency. For example, in one embodiment, the lipid-to-drug ratio is fixed, and as the amikacin concentration increases (and thus the lipid concentration increases, since the ratio of the two is fixed, for example, at about 0.7:1 by weight), the viscosity of the solution also increases, which slows the nebulization time.

[0089]

[0092] As provided throughout, the methods described herein comprise administering an effective amount of a liposomal aminoglycoside composition via inhalation to a patient in need of treatment for an NTM pulmonary infection. In one embodiment, the inhalation delivery is via a nebulizer. The nebulizer provides an aerosol mist of the composition for delivery to the patient's lungs.

[0090]

[0093] In one embodiment, the system provided herein comprises a nebulizer selected from an electronic mesh nebulizer, a pneumatic (jet) nebulizer, an ultrasonic nebulizer, a pneumatic nebulizer, and a breath-actuated nebulizer. In one embodiment, the nebulizer is portable.

[0091]

[0094] In one embodiment, the method for treating NTM infection is carried out by administering a liposome-complexed aminoglycoside composition to a patient in need thereof via a nebulizer during a once-daily dosing session. In a further embodiment, the aminoglycoside is amikacin, e.g., amikacin sulfate. In a further embodiment, the lipid components of the liposome include DPPC and cholesterol. In yet a further embodiment, the nebulizer is one of the nebulizers described in U.S. Patent Application Publication No. 2013 / 0330400, the entire contents of which are incorporated herein by reference for all purposes.

[0092]

[0095] The principles of operation of pneumonic nebulizers are generally known to those skilled in the art and are described, for example, in Respiratory Care, Vol. 45, No. 6, pp. 609-622 (2000). Briefly, a pressurized gas supply is used as the driving force for atomization of a liquid in a pneumatic nebulizer. Compressed gas is delivered, creating a region of negative pressure. The solution to be aerosolized is then delivered into the gas stream and sheared into a liquid film. This film is unstable and breaks into droplets due to surface tension. Small particles, i.e., particles with the above-mentioned MMAD and FPF properties, can then be formed by placing a baffle in the aerosol stream. In one embodiment of a pneumonic nebulizer, the gas and solution mix before exiting the exit port (nozzle) and interacting with the baffle. In another embodiment, mixing does not occur until the liquid and gas exit the exit port (nozzle). In one embodiment, the gas is air, O2, and / or CO2.

[0093]

[0096] In one embodiment, the droplet size and exit rate can be adjusted in a pneumatic nebulizer. However, consideration should be given to the composition to be nebulized and whether the composition's properties (e.g., the percentage of associated aminoglycoside) are altered by modifying the nebulizer. For example, in one embodiment, the gas velocity and / or pharmaceutical composition velocity are modified to achieve the exit rate and droplet size of the present invention. Additionally or alternatively, the gas and / or solution flow rate can be adjusted to achieve the droplet size and exit rate of the present invention. For example, in one embodiment, increasing the gas velocity decreased the droplet size. In one embodiment, the ratio of pharmaceutical composition flow to gas flow is adjusted to achieve the droplet size and exit rate of the present invention. In one embodiment, increasing the liquid to gas flow ratio increases the particle size.

[0094]

[0097] In one embodiment, the discharge rate of a pneumonics nebulizer is increased by increasing the filling volume of the liquid reservoir. Without wishing to be bound by theory, the increase in discharge rate may be due to a decrease in the dead volume within the nebulizer. In one embodiment, the nebulization time is reduced by increasing the flow to power the nebulizer. See, for example, Clay et al. (1983) Lancet 2, pp. 592-594 and Hess et al. (1996) Chest 110, pp. 498-505.

[0095]

[0098] In one embodiment, a reservoir bag is used to capture the aerosol during the nebulization process, and the aerosol is then provided to the subject via inhalation. In another embodiment, the nebulizer provided herein includes a valved open-mouth design. In this embodiment, as the patient inhales through the nebulizer, the output of the nebulizer increases. During the exhalation phase, a one-way valve diverts patient flow away from the nebulizer chamber.

[0096]

[0099] In one embodiment, the nebulizer provided herein is a continuous nebulizer. In other words, there is no need to refill the nebulizer with the pharmaceutical composition while administering the dosage. Rather, the nebulizer has a capacity of at least 8 mL or at least 10 mL.

[0097]

[0100] In one embodiment, the nebulizer provided herein does not use an air compressor and therefore does not generate an airflow. In one embodiment, the aerosol is generated by an aerosol head that enters the mixing chamber of the device. When the patient inhales, air enters the mixing chamber through a one-way inhalation valve behind the mixing chamber and carries the aerosol through the mouthpiece to the patient. When exhaling, the patient's breath flows through a one-way exhalation valve on the mouthpiece of the device. In one embodiment, the nebulizer continues to generate aerosol into the mixing chamber, which is then drawn in by the subject on the next breath; this cycle continues until the nebulizer's drug reservoir is empty.

[0098]

[0101] In one embodiment, the nebulization time for an effective amount of the aminoglycoside composition provided herein is less than 20 minutes, less than 18 minutes, less than 16 minutes, or less than 15 minutes. In one embodiment, the nebulization time for an effective amount of the aminoglycoside composition provided herein is less than 15 minutes or less than 13 minutes. In one embodiment, the nebulization time for an effective amount of the aminoglycoside composition provided herein is about 13 minutes.

[0099]

[0102] In one embodiment, the compositions described herein are administered once daily to a patient in need thereof.

[0100]

[0103] In another embodiment, a patient is treated for an NTM pulmonary infection with one of the methods and / or compositions provided herein. In a further embodiment, the composition comprises a liposomal amikacin composition. In yet a further embodiment, the composition comprises about 500 mg to about 600 mg of amikacin, DPPC, and cholesterol, wherein the lipid to aminoglycoside weight ratio of the composition is 0.75:1.0 or less, e.g., about 0.7:1.0, or about 0.5:1.0 to about 0.8:1.0.

[0101]

[0104] In one embodiment, the patient subjected to one of the treatment methods provided herein is a patient who has previously been non-responsive to a different NTM treatment. In a further embodiment, the composition administered to the patient in need of treatment is one of the compositions shown in Table 4 above.

[0102]

[0105] In one embodiment, prior to nebulization of the aminoglycoside composition, about 70% to about 100% of the aminoglycoside present in the composition is liposome-complexed. In a further embodiment, the aminoglycoside is an aminoglycoside. In yet a further embodiment, the aminoglycoside is amikacin. In another embodiment, prior to nebulization, about 80% to about 99%, or about 85% to about 99%, or about 90% to about 99%, or about 95% to about 99%, or about 96% to about 99% of the aminoglycoside present in the composition is liposome-complexed. In a further embodiment, the aminoglycoside is amikacin or tobramycin. In yet a further embodiment, the aminoglycoside is amikacin. In another embodiment, prior to nebulization, about 98% of the aminoglycoside present in the composition is liposome-complexed. In a further embodiment, the aminoglycoside is amikacin or tobramycin. In still further embodiments, the aminoglycoside is amikacin (eg, amikacin sulfate).

[0103]

[0106] In one embodiment, upon nebulization, about 20% to about 50% of the liposome-complexed aminoglycoside agent is released due to shear stress on the liposomes. In a further embodiment, the aminoglycoside agent is amikacin. In another embodiment, upon nebulization, about 25% to about 45% or about 30% to about 40% of the liposome-complexed aminoglycoside agent is released from the liposome complex due to shear stress on the liposomes. In a further embodiment, the aminoglycoside agent is amikacin. In yet a further embodiment, the amikacin is amikacin sulfate.

[0104]

[0107] Upon nebulization of a composition described herein, i.e., for administration to a patient in need of treatment for an NTM infection, an aerosolized composition is produced, and in one embodiment, the aerosolized composition has a mass median aerodynamic diameter (MMAD) of about 1.0 μm to about 4.2 μm as measured by an Andersen Cascade Impactor (ACI). In one embodiment, the aerosolized composition has a mass median aerodynamic diameter (MMAD) of about 3.2 μm to about 4.2 μm as measured by an ACI. In one embodiment, the aerosolized composition has a mass median aerodynamic diameter (MMAD) of about 1.0 μm to about 4.9 μm as measured by a Next Generation Impactor (NGI). In a further embodiment, the aerosolized composition has a mass median aerodynamic diameter (MMAD) of about 4.4 μm to about 4.9 μm as measured by an NGI.

[0105]

[0108] The fine particle fraction (FPF) of the aerosolized composition, in one embodiment, is greater than or equal to about 64% as measured by an Andersen Cascade Impactor (ACI), or greater than or equal to about 51% as measured by a Next Generation Impactor (NGI). In one embodiment, the FPF of the aerosolized composition is greater than or equal to about 70% as measured by an ACI, greater than or equal to about 51% as measured by an NGI, or greater than or equal to about 60% as measured by an NGI.

[0106]

[0109] Upon nebulization, liposomes in the pharmaceutical composition leak the drug. In one embodiment, the amount of liposome-complexed aminoglycoside after nebulization is about 45% to about 85%, or about 50% to about 80%, or about 51% to about 77%. These percentages are also referred to herein as the "percent associated aminoglycoside after nebulization." As provided herein, in one embodiment, the liposomes comprise an aminoglycoside, such as amikacin. In one embodiment, the percent associated aminoglycoside after nebulization is about 60% to about 70%. In a further embodiment, the aminoglycoside is amikacin. In another embodiment, the percent associated aminoglycoside after nebulization is about 67%, or about 65% to 70%. In a further embodiment, the aminoglycoside is amikacin. In yet a further embodiment, the amikacin is amikacin sulfate.

[0107]

[0110] In one embodiment, the percent associated aminoglycoside after nebulization is measured by collecting the aerosol from the air by condensation in a cold trap and then assaying the liquid for free and encapsulated aminoglycosides (associated aminoglycosides).

[0108]

[0111] In another embodiment, the methods provided herein are practiced for the treatment or prevention of one or more NTM pulmonary infections in a cystic fibrosis patient. In a further embodiment, the composition administered to the patient in need of treatment is one of the compositions set forth in Table 4 above.

[0109]

[0112] In one embodiment, the patient in need of treatment for an NTM lung infection is a patient with bronchiectasis. In one embodiment, the bronchiectasis is non-cystic fibrosis (CF) bronchiectasis. In another embodiment, the bronchiectasis is associated with CF in the patient in need of treatment.

[0110]

[0113] In another embodiment, the patient in need of treatment for an NTM pulmonary infection is a COPD patient. In yet another embodiment, the patient in need of treatment for an NTM pulmonary infection is an asthma patient. In a further embodiment, the composition administered to the patient in need of treatment is one of the compositions shown in Table 4 above.

[0111]

[0114] In one embodiment, the patient in need of treatment with one of the methods described herein is a cystic fibrosis patient, a bronchiectasis patient, a ciliary dyskinesia patient, a chronic smoker, a chronic obstructive pulmonary disease (COPD) patient, or a patient who has previously been non-responsive to treatment. In another embodiment, the cystic fibrosis patient is treated for an NTM lung infection with one of the methods provided herein. In yet another embodiment, the patient is a bronchiectasis patient, a COPD patient, or an asthma patient. In one embodiment, the NTM lung infection is MAC, M. kansasii, M. abscessus, or M. fortuitum. In a further embodiment, the NTM lung infection is a MAC infection.

[0112]

[0115] In one embodiment, the patient who is subjected to the methods described herein has concurrent conditions.For example, in one embodiment, the patient who needs to be treated by one of the methods described herein has diabetes, mitral valve disorder (for example, mitral valve prolapse), acute bronchitis, pulmonary hypertension, pneumonia, asthma, tracheal cancer, bronchial cancer, lung cancer, cystic fibrosis, pulmonary fibrosis, pharyngeal abnormality, tracheal abnormality, bronchial abnormality, aspergillosis, HIV or bronchiectasis.

[0113]

[0116] In one embodiment, a patient subjected to one of the NTM methods described herein exhibits negative conversion of NTM cultures during or after the administration period of the liposomal aminoglycoside composition. In one embodiment, the time to conversion is about 10 days, or about 20 days, or about 30 days, or about 40 days, or about 50 days, or about 60 days, or about 70 days, or about 80 days, or about 90 days, or about 100 days, or about 110 days. In another embodiment, the time to conversion is from about 20 days to about 200 days, from about 20 days to about 190 days, from about 20 days to about 180 days, from about 20 days to about 160 days, from about 20 days to about 150 days, from about 20 days to about 140 days, from about 20 days to about 130 days, from about 20 days to about 120 days, from about 20 days to about 110 days, from about 30 days to about 110 days, or from about 30 days to about 100 days.

[0114]

[0117] In some embodiments, the patient experiences improved pulmonary function compared to the patient's FEV1 before treatment for at least 15 days after the end of the administration period. For example, the patient may experience an increase in FEV1, an increase in blood oxygen saturation, or both. In some embodiments, the patient has an FEV1 (after the administration period or treatment cycle) that is increased by at least 5% over the FEV1 before the administration period. In other embodiments, the FEV1 is increased by 5-50% over the FEV1 before the administration period. In other embodiments, the FEV1 is increased by 25-500 mL over the FEV1 before the administration period. In some embodiments, the blood oxygen saturation is increased by at least 1% over the oxygen saturation before the administration period.

[0115]

[0118] In one embodiment, the 6-minute walk test (6MWT) is used to evaluate the effectiveness of the treatment methods provided herein. The 6MWT is a practical and simple test used to objectively assess functional exercise capacity and measures the distance a patient can walk in 6 minutes (see American Thoracic Society. (2002). Am J Respir Crit Care Med. 166, pp. 111-117, which is incorporated herein by reference in its entirety for all purposes).

[0116]

[0119] In one embodiment, a patient subjected to one of the NTM methods described herein exhibits an increased number of meters walked in the 6MWT compared to before receiving the treatment method. In one embodiment, the increased number of meters walked in the 6MWT is about 5 meters, about 10 meters, about 15 meters, about 20 meters, about 25 meters, about 30 meters, about 35 meters, about 40 meters, about 45 meters, or about 50 meters. In another embodiment, the increased number of meters walked in the 6MWT is at least about 5 meters, at least about 10 meters, at least about 15 meters, at least about 20 meters, at least about 25 meters, at least about 30 meters, at least about 35 meters, at least about 40 meters, at least about 45 meters, or at least about 50 meters. In yet another embodiment, the increased number of meters walked in the 6MWT is between about 5 meters and about 50 meters, or between about 5 meters and about 40 meters, or between about 5 meters and about 30 meters, or between about 5 meters and about 25 meters.

[0117]

[0120] In another embodiment, a patient subjected to one of the NTM methods described herein walks more meters in the 6MWT than a patient receiving nonliposomal aminoglycoside therapy. In one embodiment, the number of meters walked in the 6MWT is about 5 meters, about 10 meters, about 15 meters, about 20 meters, about 25 meters, about 30 meters, about 35 meters, about 40 meters, about 45 meters, about 50 meters, about 60 meters, about 70 meters, or about 80 meters more than a patient receiving nonliposomal aminoglycoside therapy. In another embodiment, the number of meters walked in the 6MWT is at least about 5 meters, at least about 10 meters, at least about 15 meters, at least about 20 meters, at least about 25 meters, at least about 30 meters, at least about 35 meters, at least about 40 meters, at least about 45 meters, or at least about 50 meters. In yet another embodiment, the number of meters walked in the greater 6MWT is from about 5 meters to about 80 meters, or from about 5 meters to about 70 meters, or from about 5 meters to about 60 meters, or from about 5 meters to about 50 meters.

[0118]

[0121] In one embodiment, the liposomal aminoglycoside compositions provided herein are administered to a patient in need of treatment for NTM pulmonary disease in conjunction with an additional therapy.

[0119]

[0122] In one embodiment, the liposomal aminoglycoside compositions provided herein are administered to a patient in need of treatment for NTM lung disease in combination with one or more additional therapeutic agents. In one embodiment, the one or more additional therapeutic agents are administered orally. In another embodiment, the one or more additional therapeutic agents are administered intravenously. In yet another embodiment, the one or more additional therapeutic agents are administered via inhalation.

[0120]

[0123] In one embodiment, the one or more additional therapeutic agents is a macrolide antibiotic. In a further embodiment, the macrolide antibiotic is azithromycin, clarithromycin, erythromycin, carbomycin A, josamycin, kitamycin, midecamycin, oleandomycin, solithromycin, spiramycin, troleandomycin, tylosin, roxithromycin, or a combination thereof. In a further embodiment, the macrolide antibiotic is administered orally.

[0121]

[0124] In one embodiment, the one or more additional therapeutic agents is a macrolide antibiotic, azithromycin, clarithromycin, erythromycin, or a combination thereof. In a further embodiment, the macrolide antibiotic is administered orally.

[0122]

[0125] In another embodiment, the liposomal aminoglycoside compositions provided herein are administered to a patient in need of treatment for NTM pulmonary disease together with one or more additional therapeutic agents, wherein the one or more additional therapeutic agents are rifamycin compounds. In a further embodiment, the rifamycin is rifampin. In another embodiment, the rifamycin is rifabutin, rifapentine, rifaximin, or a combination thereof.

[0123]

[0126] In a further embodiment, the one or more additional therapeutic agents is a quinolone. In a further embodiment, the quinolone is a fluoroquinolone. In another embodiment, the quinolone is ciprofloxacin, levofloxacin, gatifloxacin, enoxacin, levofloxacin, ofloxacin, moxifloxacin, trovafloxacin, or a combination thereof.

[0124]

[0127] In one embodiment, a second therapeutic agent is administered to a patient in need of NTM treatment, and the second therapeutic agent is a second aminoglycoside. In a further embodiment, the second aminoglycoside is amikacin, apramycin, arbekacin, astromycin, bekanamycin, boformycin, burramycin, capreomycin, dibekacin, dactimicin, etimicin, framycetin, gentamicin, H107, hygromycin, hygromycin B, inosamycin, K-4619, isepamicin, KA-5685, kanamycin, neomycin, netilmicin, paromomycin, plazomycin, ribostamycin, sisomicin, rhodostreptomycin, sorbistin, spectinomycin, sporalysin, streptomycin, tobramycin, verdamycin, vertilmicin, vetilmicin, a pharmaceutically acceptable salt thereof, or a combination thereof. In a further embodiment, the second aminoglycoside is administered intravenously or via inhalation. In one embodiment, the second aminoglycoside is streptomycin.

[0125]

[0128] In another embodiment, the liposomal aminoglycoside compositions provided herein are administered to a patient in need of treatment for NTM pulmonary disease along with one or more additional therapeutic agents, wherein the one or more additional therapeutic agents are ethambutol, isoniazid, cefoxitin, or imipenem. [Example]

[0126]

[0129] The present invention is further illustrated by reference to the following examples, however, as with the above embodiments, it should be noted that these examples are illustrative and should not be construed as limiting the scope of the invention in any way.

[0127] Example 1: A randomized, double-blind study of inhaled liposomal amikacin (LAI) in patients with nontuberculous mycobacterial (NTM) pulmonary disease (LD)

[0130] The increasing prevalence of NTM-LD is a public health problem, and its management, particularly in patients with cystic fibrosis, is complicated by the long-term use of multidrug regimens, drug toxicity, and poor response rates. LAI (also referred to herein as "Arikayce™" or "ARIKAYCE™") is a sustained-release lipid composition of amikacin under development for the treatment of patients with refractory NTM lung disease. This study evaluated the efficacy, safety, and tolerability of LAI in these patients in a randomized, double-blind (DB) study conducted at 19 sites in North America. Figure 1 is a flow chart illustrating the study design, and Figure 2 shows the patient distribution for this study.

[0128]

[0131] The LAI composition had the following ingredients:

[0129] [Table 5]

[0130]

[0132] Eligible NTM patients on a stable drug regimen were stratified based on the presence or absence of cystic fibrosis (CF) and Mycobacterium avium complex (MAC) versus Mycobacterium abscessus (M. abscessus) lung disease and randomized 1:1 to receive LAI 590 mg or placebo once daily via the eFlow® nebulizer system (PARI Pharma GmbH) for 84 days in addition to their ongoing stable drug regimen. Figure 3 shows the number of patients in each group (randomized by strata). Patients were eligible for enrollment if they had an NTM lung infection refractory to American Thoracic Society / Infectious Diseases Society of America (ATS / IDSA) guideline-based therapy for ≥6 months prior to screening.

[0131]

[0133] After completion of the double-blind (DB) phase, patients who accepted the open-label (OL) phase received LAI 590 mg once daily for an additional 84 days (Figures 1 and 2).

[0132]

[0134] Of 136 patients screened, 90 were randomized (19% CF; 81% non-CF; 64% with MAC and 36% with M. abscessus). 54% of patients were over 60 years old; 31% were over 40 to 60 years old, and 14% were between 18 and 40 years old. The mean age at baseline was 58.5 years (standard deviation, 15.83 years).

[0133]

[0135] 80 and 59 patients will complete the DB and OL phases, respectively, to complete the study. The demographics and baseline characteristics of the mITT population are provided in Table 5 below.

[0134] [Table 6]

[0135]

[0136] The sample population enrolled in the mITT trial showed the following: (1) concomitant lung disease, with 17 of the patients having cystic fibrosis; (2) a mean age of 59 years, including younger cystic fibrosis patients; (3) pulmonary abnormalities, including 68 patients with cavitary lesions and 21 patients with nodular disease, which further included microcavitary disease; (4) a mean body mass index (BMI) of 21.98, whereas comparable CDC data collected between 2007 and 2010 revealed that the mean U.S. BMI was 28.6 for adult men and 28.7 for adult women; and (5) a mean baseline 6-minute walk distance of approximately 441 m for all patients, with both arms having approximately the same mean baseline.

[0136]

[0137] Sputum for semiquantitative mycobacterial culture, smear status, signs / symptoms, pulmonary exacerbation, antimycobacterial rescue, 6-minute walk distance (6MWD), chest computed tomography, spirometry, clinical / laboratory safety parameters, and quality of life measures were assessed every 28 days. The primary endpoint was the change from baseline in semiquantitative measures for mycobacterial culture; the secondary endpoint was the proportion of patients with negative NTM cultures for LAI vs. placebo at day 84. All patients returned for safety follow-up 28 days after the last dose of study drug, and until day 196 for patients in the OL phase.

[0137]

[0138] Figure 4 is a graph showing the mean change from baseline in the complete semiquantitative scale of mycobacterial cultures (mITT population) as a function of study day during both the double-blind and open-label phases of the study. As shown in the figure, patients treated with LAIs showed at least a one-grade reduction in the treatment arm vs. the placebo arm during the double-blind phase.

[0138]

[0139] The proportion of patients (mITT population) with negative sputum cultures for NTM at days 84 and 168 in each subgroup by treatment arm is summarized in Tables 6–8. Among patients who achieved negative sputum cultures for NTM at day 84, statistically significant between-group differences for LAI versus placebo were seen in patients with non-CF infections (P = .01), MAC infections (P = .017), females (P = .004), whites (P = .031), and patients younger than 63 years (P = .041) (Table 6).

[0139]

[0140] At day 168, statistically significantly more patients with MAC infection had NTM-negative sputum cultures in the prior LAI arm versus the prior placebo arm (P = .026) (Table 6). In analyses of the subgroup of patients with NTM lung infections refractory to guideline-based therapy (Tables 7 and 8), LAI appeared superior to placebo with respect to NTM-negative sputum cultures in patients with non-CF underlying lung disease and MAC infection. The subgroup of patients with non-CF MAC infections demonstrated positive efficacy results within the study timeframe (i.e., the 12-week double-blind phase and the 12-week open-label phase).

[0140]

[0141] Time to culture conversion demonstrated a statistically significantly higher proportion of patients in the LAI arm who achieved negative cultures at all visits during the double-blind phase (days 28, 56, and 84) (Figure 5, top panel). Specifically, LAI achieved statistical significance in achieving negative cultures at day 84, with 11 of 44 patients in the LAI arm versus 3 of 45 patients in the placebo arm (P = .01) (Figure 5, top panel). Compared with placebo, LAI achieved statistical significance for the proportion of patients with MAC infections who achieved negative cultures at day 56 (LAI, 10 / 29 patients vs. placebo, 2 / 28 patients; P = .0144) and day 84 (LAI, 10 / 29 patients vs. placebo, 3 / 28 patients; P = .0273) (Figure 5, bottom panel).

[0141]

[0142] In patients refractory to NTM regimens for at least 6 months, LAI, an inhaled amikacin composition, resulted in significantly higher culture conversion within 84 days compared to placebo. Patients with at least one NTM culture-negative result are presented in Figure 6.

[0142] [Table 7]

[0143] [Table 8]

[0144] [Table 9]

[0145] The 6-minute walk test (6MWT) assessed the impact of LAI on overall physical function or capacity. The 6MWT endpoint results (change from baseline from day 1 to day 84, the final day of the double-blind study) are provided in Figures 7 and 8. LAI demonstrated statistical significance for the 6MWT in the double-blind phase (LAI vs. placebo: 23.895 vs. -25.032 meters, P = 0.009). The mean change in distance walked (meters) in the 6MWT from baseline to day 84 was significantly higher in patients receiving LAI compared with placebo (20.64 m vs. -25.03 m) (Figure 7, bottom panel). During the open-label phase, patients in the LAI arm continued to improve in the 6MWT, and patients in the placebo group who initiated LAI showed a dramatic reduction in the rate of deterioration (Figures 7 and 8). Furthermore, a significant difference in the mean change in 6MWT score from baseline to day 168 was observed in patients who remained culture-negative until the end of the Orplan label phase compared with patients who did not remain culture-negative (55.75 m vs. -13.42 m) (Figure 8, bottom panel).

[0146] Patients with treatment-refractory NTM lung infections showed improvement in walking distance in the 6MWT when LAI was added to the background of their guideline-based therapy. Patients who remained culture-negative throughout the study achieved better physical functional capacity as assessed by the 6MWT.

[0147]

[0145] The sample population enrolled in the mITT trial showed the following with respect to culture conversion, measured as three consecutive negative sputum cultures before day 168: (1) a total of 16 patients, all of whom were non-cystic fibrosis, showed culture conversion; (2) 15 patients had MAC and 1 had M. abscessus; (3) despite more than 24 months of non-LAI treatment, 8 patients did not show treatment success, despite 12-24 months of non-LAI treatment, and 4 patients did not show treatment success, despite 6-12 months of non-LAI treatment. (4) Seven patients showed nodular disease, two patients showed nodular disease and microcavitary disease, and seven patients showed cavitary disease; (5) 11 patients began conversion on or before day 56 after initiating the LAI treatment regimen, two patients converted on day 84 after initiating the LAI treatment regimen, and three patients converted on day 112 after initiating the LAI treatment regimen; and (6) the 6MWT for converters (n=16) vs. non-converters (n=43) at day 168 was 89.34 meters (converters) vs. 3.85 meters (non-converters) with a p-value of 0.0034.

[0148]

[0146] There were no differences between arms in patients with hemoptysis, tinnitus and hearing loss.

[0149] Furthermore, patients entering the open-label phase from LAI in the double-blind phase (see Figure 1 for study design) were found to have continued improvement. Furthermore, patients entering the open-label phase from placebo show a dramatic reduction in their rate of decline. Treatment-emergent adverse events (TEAEs) were mostly mild or moderate in severity, with the majority of TEAEs being respiratory in nature (Table 9). Local events and infectious exacerbations of underlying pulmonary disease were the most common TEAEs. A small number of patients discontinued study drug due to these events.

[0150] [Table 10]

[0151] Example 2: Study of inhaled liposomal amikacin (LAI) in patients with non-CF M. avium complex (MAC) pulmonary infections LAI (also referred to herein as "Arikayce™" or "ARIKAYCE™") is a sustained-release lipid composition of amikacin in development for the treatment of patients with refractory NTM lung disease. In this study, the efficacy, safety, and tolerability of LAI will be evaluated in non-cystic fibrosis patients with M. avium complex (MAC) pulmonary infection. Figure 9 is a flow chart illustrating the study design.

[0152]

[0149] The LAI composition includes the following ingredients:

[0153] [Table 11]

[0154]

[0150] Table 10 provides the inclusion criteria for this study.

[0155] [Table 12]

[0156] Patients will be randomized 2:1 to two groups: (i) LAI 590 mg + background therapy and (ii) background therapy only. Each patient group will receive daily medication for 8 months. Primary culture conversion will be assessed at 6 months. A 6MWT will also be performed for each patient at 6 months.

[0157]

[0152] Culture converters continue treatment for 12 months after conversion.

[0158]

[0153] All documents, patents, patent applications, publications, product descriptions and protocols cited throughout this application are hereby incorporated by reference in their entirety for all purposes.

[0159]

[0154] The embodiments illustrated and discussed herein are intended only to teach those skilled in the art the best way known to the inventors to make and use the invention. As will be appreciated by those skilled in the art in light of the above teachings, improvements and modifications to the above embodiments of the invention are possible without departing from the invention. It is therefore to be understood that, within the scope of the claims and their equivalents, the invention may be practiced other than as specifically described. Accordingly, the foregoing description and drawings are by way of example only, and the disclosure is more particularly set forth in the following claims.

Claims

1. 1. A method for treating or providing prophylaxis against a nontuberculous mycobacterial (NTM) pulmonary infection in a patient in need thereof, comprising: administering to the patient's lungs for an administration period a pharmaceutical composition comprising an aminoglycoside or a pharmaceutically acceptable salt thereof encapsulated in a plurality of liposomes, wherein the lipid component of said plurality of liposomes comprises one or more electrically neutral lipids; administering to the patient's lungs comprises aerosolizing a pharmaceutical composition to provide an aerosolized pharmaceutical composition comprising a mixture of free aminoglycosides and liposome-complexed aminoglycosides, and administering the aerosolized pharmaceutical composition to the patient's lungs via a nebulizer; A method wherein during or after said administration period, the patient experiences a change from baseline in a complete semi-quantitative measure of mycobacterial cultures and / or a negative conversion of NTM cultures during or after the administration period.

2. 1. A method for treating or providing prophylaxis against a nontuberculous mycobacterial (NTM) pulmonary infection in a patient in need thereof, comprising: administering to the patient's lungs for an administration period a pharmaceutical composition comprising an aminoglycoside or a pharmaceutically acceptable salt thereof encapsulated in a plurality of liposomes, wherein the lipid component of said plurality of liposomes is comprised of one or more electrically neutral lipids; administering to the patient's lungs comprises aerosolizing a pharmaceutical composition to provide an aerosolized pharmaceutical composition comprising a mixture of free aminoglycosides and liposome-complexed aminoglycosides, and administering the aerosolized pharmaceutical composition to the patient's lungs via a nebulizer; During or after said administration period, the patient exhibits an increased number of meters walked in a 6-minute walk test (6MWT) compared to the number of meters walked by the patient before receiving the treatment method.

3. 1. A method for treating or providing prophylaxis against a nontuberculous mycobacterial (NTM) pulmonary infection in a patient in need thereof, comprising: administering to the patient's lungs for an administration period a pharmaceutical composition comprising an aminoglycoside or a pharmaceutically acceptable salt thereof encapsulated in a plurality of liposomes, wherein the lipid component of said plurality of liposomes is comprised of one or more electrically neutral lipids; administering to the patient's lungs comprises aerosolizing a pharmaceutical composition to provide an aerosolized pharmaceutical composition comprising a mixture of free aminoglycosides and liposome-complexed aminoglycosides, and administering the aerosolized pharmaceutical composition to the patient's lungs via a nebulizer; During or after said administration period, the patient exhibits a greater number of meters walked in 6MWT than patients subjected to nonliposomal aminoglycoside treatment for NTM pulmonary infections.

4. 1. A method for treating or providing prophylaxis against a nontuberculous mycobacterial (NTM) pulmonary infection in a patient in need thereof, comprising: administering to the patient's lungs for an administration period a pharmaceutical composition comprising an aminoglycoside or a pharmaceutically acceptable salt thereof encapsulated in a plurality of liposomes, wherein the lipid component of said plurality of liposomes is comprised of one or more electrically neutral lipids; administering to the patient's lungs comprises aerosolizing a pharmaceutical composition to provide an aerosolized pharmaceutical composition comprising a mixture of free aminoglycosides and liposome-complexed aminoglycosides, and administering the aerosolized pharmaceutical composition to the patient's lungs via a nebulizer; Patients were monitored for at least 15 days after the end of the treatment period to determine their pre-treatment FEV １ Compared to FEV １ How to experience improvements.

5. 5. The method of any one of claims 1 to 4, wherein the aminoglycoside or a pharmaceutically acceptable salt thereof is amikacin, apramycin, arbekacin, astromycin, bekanamycin, boformycin, burramycin, capreomycin, dibekacin, dactimycin, etimicin, framycetin, gentamicin, H107, hygromycin, hygromycin B, inosamycin, K-4619, isepamicin, KA-5685, kanamycin, neomycin, netilmicin, paromomycin, plazomycin, ribostamycin, sisomicin, rhodostreptomycin, sorbistin, spectinomycin, sporalysin, streptomycin, tobramycin, verdamycin, vertilmicin, a pharmaceutically acceptable salt thereof, or a combination thereof.

6. The method of any one of claims 1 to 4, wherein the aminoglycoside or a pharmaceutically acceptable salt thereof is amikacin.

7. The method according to any one of claims 1 to 4, wherein the aminoglycoside or a pharmaceutically acceptable salt thereof is amikacin sulfate.

8. The method of any one of claims 1 to 7, wherein the plurality of liposomes comprises unilamellar vesicles, multilamellar vesicles, or a combination thereof.

9. The method according to any one of claims 1 to 8, wherein the electrically neutral lipid comprises an electrically neutral phospholipid or an electrically neutral phospholipid and a sterol.

10. The method according to any one of claims 1 to 9, wherein the electrically neutral lipid comprises a phosphatidylcholine and a sterol.

11. The method according to any one of claims 1 to 10, wherein the electrically neutral lipid comprises dipalmitoylphosphatidylcholine (DPPC) and a sterol.

12. The method according to any one of claims 1 to 10, wherein the electrically neutral lipid comprises DPPC and cholesterol.

13. 13. The method of any one of claims 1 to 12, wherein the aminoglycoside is amikacin, the electrically neutral lipid comprises DPPC and cholesterol, and the liposome comprises a unilamellar vesicle, a multilamellar vesicle, or a mixture thereof.

14. 14. The method of any one of claims 1 to 13, wherein the volume of the pharmaceutical composition administered to the patient is from about 8 mL to about 10 mL.

15. 15. The method of any one of claims 1 to 14, wherein the pharmaceutical composition comprises about 500 mg to about 650 mg of an aminoglycoside or a pharmaceutically acceptable salt thereof, or about 550 mg to about 625 mg of an aminoglycoside or a pharmaceutically acceptable salt thereof, or about 550 mg to about 600 mg of an aminoglycoside or a pharmaceutically acceptable salt thereof.

16. The method of any one of claims 1 to 15, wherein the pharmaceutical composition is an aqueous dispersion.

17. 17. The method of any one of claims 1 to 16, wherein the pharmaceutical composition comprises about 70 to about 75 mg / mL of amikacin or a pharmaceutically acceptable salt thereof; about 32 to about 35 mg / mL of DPPC; and about 16 to about 17 mg / mL of cholesterol.

18. 18. The method of any one of claims 1 to 17, wherein the pharmaceutical composition has a volume of about 8 mL.

19. 19. The method of any one of claims 1-18, wherein the aerosolized pharmaceutical composition is administered once daily in a single dosing session for the administration period.

20. 20. The method of any one of claims 1-19, wherein the aerosolized pharmaceutical composition is administered in less than about 15 minutes, less than about 14 minutes, less than about 13 minutes, less than about 12 minutes, or less than about 11 minutes during a single dosing session.

21. 21. The method of any one of claims 1-20, wherein during a single dosing session, the aerosolized pharmaceutical composition is administered in about 10 minutes to about 14 minutes, about 10 minutes to about 13 minutes, about 10 minutes to about 12 minutes, about 10 minutes to about 11 minutes, about 11 minutes to about 15 minutes, about 12 minutes to about 15 minutes, about 13 minutes to about 15 minutes, or about 14 minutes to about 15 minutes.

22. 22. The method of any one of claims 1-21, wherein about 25% to about 35% of the aerosolized pharmaceutical composition is deposited in the bronchial and alveolar regions of the patient's lungs.

23. 23. The method of any one of claims 1 to 22, wherein the patient in need of said treatment or prevention has cystic fibrosis.

24. The method of any one of claims 1 to 23, wherein the patient in need of said treatment or prevention has bronchiectasis.

25. The method according to any one of claims 1 to 24, wherein the patient in need of said treatment or prevention is a smoker or has a history of smoking.

26. 26. The method of any one of claims 1 to 25, wherein the patient in need of said treatment or prevention has chronic obstructive pulmonary disease (COPD).

27. The method of any one of claims 1 to 26, wherein the patient in need of said treatment or prevention has asthma.

28. 28. The method of any one of claims 1 to 27, wherein the patient in need of said treatment or prevention has previously been non-responsive to NTM therapy.

29. The method according to any one of claims 1 to 28, wherein the patient in need of said treatment or prevention is a patient with ciliary dyskinesia.

30. 30. The method of any one of claims 1 to 29, wherein the patient in need of said treatment or prevention has, in addition to an NTM pulmonary infection, a co-occurring condition selected from diabetes, mitral valve disorders, acute bronchitis, pulmonary hypertension, pneumonia, asthma, tracheal carcinoma, bronchial carcinoma, lung cancer, cystic fibrosis, pulmonary fibrosis, pharyngeal abnormalities, tracheal abnormalities, bronchial abnormalities, aspergillosis, HIV, or bronchiectasis.

31. 31. The method of claim 30, wherein the mitral valve disorder is mitral valve prolapse.

32. 32. The method of any one of claims 1 to 31, wherein the NTM pulmonary infection is an M. avium infection.

33. 33. The method of claim 32, wherein the M. avium infection is a Mycobacterium avium subsp. hominiss infection.

34. 32. The method of any one of claims 1 to 31, wherein the NTM lung infection is a Mycobacterium abscessus infection.

35. 32. The method of any one of claims 1 to 31, wherein the NTM pulmonary infection is Mycobacterium avium complex (M. avium and M. intracellulare).

36. NTM lung infection is caused by M. avium, M. avium subsp. hominissuis (MAH), M. abscessus, M. chelonae, M. bolletii, M. kansasii, M. ulcerans, M. avium, M. avium complex (MAC) (M. avium and M. intracellulare), M. avium complex (MAC) (M. avium and M. intracellulare). conspicuum, M. kansasii, M. peregrinum, M. immunogenum, M. xenopi, M. marinum, M. malmoense, M. marinum, M. mucogenicum, M. nonchromogenicum, M. scrofulaceum, M. simiae, M. smegmatis, M. szulgai, M. terrae, M. terrae complex, M. haemophilum, M. genavense, M. asiaticum, M. shimoidei, M. gordonae, M. nonchromogenicum, M. triplex, M. lentiflavum, M. celatum, M. fortuitum, M. The method according to any one of claims 1 to 31, wherein the fungus is M. fortuitum complex (M. fortuitum and M. chelonae), or a combination thereof.

37. The method according to any one of claims 1 to 36, wherein the NTM pulmonary infection is an NTM pulmonary infection having symptoms similar to hypersensitivity lung disease.

38. The method of any one of claims 1 to 36, wherein the NTM pulmonary infection is a macrolide-resistant NTM pulmonary infection.

39. 39. The method of any one of claims 1 to 38, further comprising administering to a patient in need of said treatment or prevention one or more additional therapeutic agents.

40. 40. The method of claim 39, wherein the one or more additional therapeutic agents is a macrolide antibiotic.

41. 41. The method of claim 40, wherein the macrolide antibiotic is azithromycin, clarithromycin, erythromycin, carbomycin A, josamycin, kitamycin, midecamycin, oleandomycin, solithromycin, spiramycin, troleandomycin, tylosin, roxithromycin, or a combination thereof.

42. 41. The method of claim 40, wherein the macrolide antibiotic is azithromycin.

43. 41. The method of claim 40, wherein the macrolide antibiotic is clarithromycin.

44. 41. The method of claim 40, wherein the macrolide antibiotic is erythromycin.

45. 45. The method of any one of claims 40 to 44, wherein the macrolide antibiotic is administered orally.

46. 40. The method of claim 39, wherein the one or more additional therapeutic agents is a rifamycin.

47. 47. The method of claim 46, wherein the rifamycin is rifampin.

48. 47. The method of claim 46, wherein the rifamycin is rifabutin, rifapentine, rifaximin, or a combination thereof.

49. 40. The method of claim 39, wherein the one or more additional therapeutic agents is a quinolone.

50. 50. The method of claim 49, wherein the quinolone is a fluoroquinolone.

51. 40. The method of claim 39, wherein the one or more additional therapeutic agents is a second aminoglycoside.

52. 52. The method of claim 51, wherein the second aminoglycoside is amikacin, apramycin, arbekacin, astromycin, bekanamycin, boformycin, burramycin, capreomycin, dibekacin, dactimicin, etimicin, framycetin, gentamicin, H107, hygromycin, hygromycin B, inosamycin, K-4619, isepamicin, KA-5685, kanamycin, neomycin, netilmicin, paromomycin, plazomycin, ribostamycin, sisomicin, rhodostreptomycin, sorbistin, spectinomycin, sporalysin, streptomycin, tobramycin, verdamycin, vertilmicin, a pharmaceutically acceptable salt thereof, or a combination thereof.

53. 53. The method of claim 52, wherein the second aminoglycoside is administered intravenously.

54. 53. The method of claim 52, wherein the second aminoglycoside is administered via inhalation.

55. 55. The method of any one of claims 51 to 54, wherein the second aminoglycoside is streptomycin.

56. 40. The method of claim 39, wherein the one or more additional therapeutic agents is ethambutol.

57. 40. The method of claim 39, wherein the one or more additional therapeutic agents is isoniazid.

58. 40. The method of claim 39, wherein the one or more additional therapeutic agents is cefoxitin.

59. 40. The method of claim 39, wherein the one or more additional therapeutic agents is imipenem.

60. 40. The method of claim 39, wherein the one or more additional therapeutic agents is tigecycline.

61. 50. The method of claim 49, wherein the quinolone is ciprofloxacin.

62. 50. The method of claim 49, wherein the quinolone is levofloxacin.

63. 50. The method of claim 49, wherein the quinolone is gatifloxacin.

64. 50. The method of claim 49, wherein the quinolone is enoxacin.

65. 50. The method of claim 49, wherein the quinolone is levofloxacin.

66. 50. The method of claim 49, wherein the quinolone is ofloxacin.

67. 50. The method of claim 49, wherein the quinolone is moxifloxacin.

68. 50. The method of claim 49, wherein the quinolone is trovafloxacin.

69. 69. The method of any one of claims 1 to 68, wherein during or after the administration period, the patient exhibits a negative conversion of NTM cultures.

70. 70. The method of claim 69, wherein the time to negative conversion of the NTM culture is about 10 days, about 20 days, about 30 days, about 40 days, about 50 days, about 60 days, about 70 days, about 80 days, about 90 days, about 100 days, or about 110 days.

71. 70. The method of claim 69, wherein the time to negative conversion of the NTM culture is between about 20 days and about 200 days, between about 20 days and about 190 days, between about 20 days and about 180 days, between about 20 days and about 160 days, between about 20 days and about 150 days, between about 20 days and about 140 days, between about 20 days and about 130 days, between about 20 days and about 120 days, between about 20 days and about 110 days, between about 30 days and about 110 days, or between about 30 days and about 100 days.

72. Patients should maintain a FEV1 level that is comparable to that of the patients before the treatment period for at least 15 days after the treatment period. １ Compared to FEV １ 72. The method of any one of claims 1 to 71, wherein the method experiences an improvement in

73. 73. The method of any one of claims 1-72, wherein the patient experiences an improvement in blood oxygen saturation compared to the patient's blood oxygen saturation prior to the administration period for at least 15 days after the administration period ends.

74. Patient's FEV １ However, the patient's FEV before the administration period １ 73. The method of claim 72, wherein the increase is at least 5%.

75. Patient's FEV １ However, the patient's FEV before the administration period １ 73. The method of claim 72, wherein the increase is at least 10%.

76. Patient's FEV １ However, the patient's FEV before the administration period １ 73. The method of claim 72, wherein the increase is at least 15%.

77. Patient's FEV １ However, FEV before the administration period １ 73. The method of claim 72, wherein the amount of hydroxylase is increased by 5% to 50%.

78. 78. The method of any one of claims 1 to 77, wherein the patient exhibits an increased number of metres walked in a 6 minute walk test (6MWT) compared to the number of metres walked by the patient before receiving the treatment method.

79. 79. The method of claim 78, wherein the number of meters walked at an increased 6MWT is, in one embodiment, at least about 5 meters.

80. 79. The method of claim 78, wherein the number of meters walked at an increased 6MWT is, in one embodiment, at least about 10 meters.

81. 79. The method of claim 78, wherein the number of meters walked at an increased 6MWT is, in one embodiment, at least about 20 meters.

82. 79. The method of claim 78, wherein the number of meters walked at an increased 6MWT is, in one embodiment, at least about 30 meters.

83. 79. The method of claim 78, wherein the number of meters walked at an increased 6MWT is, in one embodiment, at least about 40 meters.

84. 79. The method of claim 78, wherein the number of meters walked at an increased 6MWT is, in one embodiment, at least about 50 meters.

85. 79. The method of claim 78, wherein the number of meters walked at an increased 6MWT is, in one embodiment, from about 5 meters to about 50 meters.

86. 79. The method of claim 78, wherein the number of meters walked at an increased 6MWT is, in one embodiment, from about 15 meters to about 50 meters.

87. 87. The method of any one of claims 1 to 86, wherein the patient exhibits a greater number of meters walked in 6MWT compared to patients subjected to non-liposomal aminoglycoside treatment for NTM pulmonary infections.

88. 88. The method of claim 87, wherein the greater number of meters is at least about 5 meters, at least about 10 meters, at least about 15 meters, at least about 20 meters, at least about 25 meters, at least about 30 meters, at least about 35 meters, at least about 40 meters, at least about 45 meters, or at least about 50 meters.

89. 88. The method of claim 87, wherein the greater number of meters is from about 5 meters to about 80 meters, from about 5 meters to about 70 meters, from about 5 meters to about 60 meters, or from about 5 meters to about 50 meters.

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