Methods for treating nontuberculous mycobacterial lung 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]

[0001] Cross - Reference to Related Applications This application claims priority from U.S. Provisional Application No. 61 / 993,439, filed on May 15, 2014; No. 62 / 042,126, filed on August 26, 2014; No. 62 / 048,068, filed on September 9, 2014; and No. 62 / 056,296, filed on September 26, 2014, the entire disclosures of each of which are incorporated by reference for all purposes.

Background Art

[0002]

[0002] Certain techniques suitable for administration by inhalation use liposomes, and the lipid complexes provide an extended therapeutic effect of the drug in the lungs. These techniques also provide drugs that have the ability to target and promote sustained activity and uptake of the drug at the disease site.

[0003]

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

[0004]

[0004] Pulmonary infections caused by nontuberculous mycobacteria (NTM) in susceptible hosts can result in morbidity and even mortality that can worsen among infected individuals. Due to the increasing infection rate, nontuberculous mycobacterial pulmonary disease (PNTM) is emerging as a public health concern in the United States. NTM are present everywhere in the environment. More than 80% of NTM pulmonary (PNTM) infections in the United States are due to Mycobacterium avium complex (MAC). Additionally, M. Kansasii, M. abscessus, and M. fortuitum are commonly isolated.

[0005]

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

[0006]

[0006] In susceptible individuals, NTM lung infection can be severe or life-threatening. Available treatments may be poorly tolerable and may have significant adverse events. The present invention addresses this and other needs by providing a method for treating NTM lung infection in patients who need it. [Overview of the project] [Means for solving the problem]

[0007]

[0007] In one embodiment, the present invention provides a method for treating or preventing nontuberculous mycobacterial (NTM) infection (a lung infection caused by or resulting from one or more nontuberculous mycobacteria) by inhalation administration of an effective amount of a composition comprising a liposome-conjugated aminoglycoside or a pharmaceutically acceptable salt thereof to a patient in need thereof. In one embodiment, the patient in need of treatment is a patient with cystic fibrosis, a patient with bronchiectasis, a patient with asthma, or a patient with 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. The NTM pulmonary infection is selected from M. fortuitum and M. chelonae infections or combinations thereof. In a further embodiment, the NTM infection is M. avium complex (MAC) (M. avium and M. intracellulare) infection. In one embodiment, the NTM infection is a refractory NTM pulmonary infection.

[0009]

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

[0010]

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

[0011]

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

[0012]

[0012] In one embodiment, the aminoglycoside or a pharmaceutically acceptable salt thereof is amikacin, apramycin, arbekacin, astromycin, capreomycin, dibekacin, flamycetin, gentamicin, hygromycin B, isepamycin, kanamycin, neomycin, netylmycin, paromomycin, rhodostreptomycin, ribostamycin, shisomycin, spectinomycin, streptomycin, tobramycin, verdamycin, or a pharmaceutically acceptable salt thereof or a combination thereof. In a further embodiment, the aminoglycoside is amikacin. In another embodiment, the aminoglycoside is selected from the aminoglycosides, pharmaceutically acceptable salts thereof or combinations thereof shown in Table 1 below.

[0013] [Table 1]

[0014]

[0013] In one embodiment, the pharmaceutical composition provided herein is a liposome dispersion (i.e., a liposome dispersion or aqueous liposome dispersion, which may be either a liposome solution or a liposome 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 lipids include phospholipids and sterols. In a further embodiment, the phospholipid is dipalmitoylphosphatidylcholine (DPPC) and the sterol is cholesterol.

[0015]

[0014] In one embodiment, the weight ratio of lipids to aminoglycosides 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 lipids to aminoglycosides 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]

[0015] In one embodiment, the method provided herein includes administration of a liposome aminoglycoside composition via atomization or aerosolization. Thus, the method in this embodiment involves the production of an aerosolized aminoglycoside composition. In one embodiment, upon atomization, the aerosolized composition has aerosol droplet sizes of about 1 μm to about 3.8 μm, about 1.0 μm to about 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 a further embodiment, the amikacin is amikacin sulfate.

[0017]

[0016] In one embodiment, about 70% to about 100% of the aminoglycoside present in the composition is liposomally complexed, for example, encapsulated in multiple liposomes, before 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 (for example, as amikacin sulfate). In a further embodiment, about 80% to about 100% of the amikacin is liposomally complexed or about 80% to about 100% of the amikacin is encapsulated in multiple liposomes before administration to a patient in need of treatment. In another embodiment, before administration to a patient requiring treatment (i.e., before spraying), 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 aminoglycosides present in the composition are liposome-conjugated.

[0018]

[0017] In one embodiment, the percentage of aminoglycosides complexed with liposomes after atomization (also referred to herein as "liposome-associated") 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 further embodiments, the aminoglycoside is selected from the aminoglycosides provided in Table 1. In further embodiments, the aminoglycoside is amikacin. In further embodiments, amikacin is amikacin sulfate. In one embodiment, the aerosolized (i.e., after atomization) composition contains about 65% to about 75% liposome-associated aminoglycosides and about 25% to about 35% free aminoglycosides. In further embodiments, the aminoglycoside is amikacin. In further embodiments, amikacin is amikacin sulfate.

[0019]

[0018] In one embodiment, the lung infection treated by the method provided herein is Mycobacterium abscessus lung infection or Mycobacterium avium complex lung infection. In one or more of the preceding embodiments, the patient is a patient with cystic fibrosis, a patient with bronchiectasis, a patient with asthma, or a patient with COPD.

[0020]

[0019] In one embodiment, a patient having cystic fibrosis is treated with one of the compositions or systems provided herein for the treatment of a pulmonary infection. In a further embodiment, the pulmonary infection is caused by Mycobacterium abscessus or Mycobacterium avium complex.

[0021]

[0020] In one embodiment, the concentration of aminoglycoside in the liposome aminoglycoside composition is about 50 mg / mL or more. In a further embodiment, the concentration of aminoglycoside in the liposome-complexed aminoglycoside is about 60 mg / mL or more. In a further embodiment, the concentration of aminoglycoside in the liposome-complexed aminoglycoside is about 70 mg / mL or more, for example, 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 a further embodiment, the aminoglycoside is amikacin (for example, amikacin sulfate). [Brief explanation of the drawing]

[0022] [Figure 1]

[0021] This figure shows the study design of a randomized, double-blind, placebo-controlled trial of liposome-conjugated amikacin in patients with refractory non-tuberculous mycobacteria (NTM) pulmonary infection, as described in Example 1. [Figure 2]

[0022] This figure shows the patient distribution for a randomized, double-blind, placebo-controlled trial of liposome-conjugated amikacin in patients with refractory non-tuberculous mycobacterial lung infection, as described in Example 1. [Figure 3]

[0023] It is a graph showing the number of patients in each NTM treatment group. [Figure 4]

[0024] Graph showing the mean change from baseline on a logarithmic scale of a complete semi - quantitative measure of mycobacterial culture as a function of the test day, for the modified intent to treat patient (mITT) population, regarding both the double - blind and open - label phases of the trial shown in Example 1. [Figure 5]

[0025] Figure 5 (upper figure) is a bar graph showing the percentage of patients with NTM culture conversion to negative at various time points during a randomized double - blind placebo - controlled trial (modified intent - to - treat population). Figure 5 (lower figure) is a bar graph showing the percentage of MAC patients with NTM culture conversion to negative at various time points. [Figure 6]

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

[0027] Figure 7 (upper figure) is a graph showing the change from baseline in the 6 - minute walk test at day 84 and day 168 (mITT population), and Figure 7 (lower figure) is a graph of the mean change from baseline in walking distance (meters) in the 6MWT for patients receiving LAI at day 84 versus patients receiving placebo (last - observation - carried - forward, modified intent - to - treat population). [Figure 8]

[0028] Figure 8 (upper figure) is a graph showing the average meters walked in the 6 - minute walk test at day 84 and day 168 (all patients). Figure 8 (lower figure) is a graph of the mean change from baseline in walking distance (meters) in the 6MWT from day 84 to day 168 for patients with culture conversion to negative (three or more negative cultures) versus patients without culture conversion to negative (last - observation - carried - forward, modified intent - to - treat population). [Figure 9]

[0029] This figure shows the study design of a randomized, placebo-controlled trial of liposome-encapsulated amikacin (ARIKAYCE or LAI) in patients with non-cystic fibrotic (non-CF) M. avium complex (MAC) pulmonary infection described in Example 2. [Modes for carrying out the invention]

[0023]

[0030] The invention described herein, in part, relates to a method for treating pulmonary infections in patients in need, for example, administering an aminoglycoside pharmaceutical composition to the patient's lungs, for example, by spraying.

[0024]

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

[0025]

[0032] The term “to treat” includes: (1) preventing or delaying the onset of clinical symptoms of a condition, disorder, or state in a subject who is likely to suffer from or be predisposed to such condition, but has not yet experienced or presented any clinical or subclinical symptoms of such condition; (2) preventing the condition (i.e., stopping, 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) mitigating the condition (i.e., causing a reduction in the condition, disorder, or state, or at least one clinical or subclinical symptom thereof). The benefit to the subject being treated is statistically significant or at least perceptible to the subject or the physician.

[0026]

[0033] As used herein, “prevention” may mean the complete prevention of an infectious disease or illness, or the prevention of the onset of symptoms of such infectious disease or illness; the delay of the onset of an infectious disease or illness or its symptoms; or a reduction in the severity of any subsequent infectious disease or illness or its symptoms.

[0027]

[0034] The term “antimicrobial” is approved in this art and refers to the ability of the compounds of this invention to prevent, inhibit, or destroy the growth of bacterial microorganisms. Examples of bacteria are provided above.

[0028]

[0035] The term "antimicrobial" is approved in this field and refers to the ability of the aminoglycoside compounds of the present invention to prevent, inhibit, delay or destroy the growth of microorganisms such as bacteria, fungi, protozoa, and viruses.

[0029]

[0036] "Effective amount" means the amount of aminoglycoside (e.g., amikacin) used in the present invention that is sufficient to produce the desired therapeutic response. The effective amount of the compositions provided herein includes both free and liposomal-conjugated aminoglycosides. For example, in one embodiment, liposomal-conjugated aminoglycosides include aminoglycosides encapsulated in liposomes or complexed with liposomes, or a combination thereof.

[0030]

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

[0031]

[0038] As used herein, "aerosol" refers to a gaseous suspension of liquid particles. The aerosols provided herein include particles of a liposome 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 airway. Pneumonic, ultrasonic, and electronic nebulizers, such as passive electronic mesh nebulizers, active electronic mesh nebulizers, and vibrating mesh nebulizers, are suitable for use with the present invention if the particular nebulizer releases an aerosol having the required properties at the required discharge rate.

[0033]

[0040] The process of converting bulk liquid into small droplets using air pressure is called atomization. Operation of a pneumatic nebulizer requires a supply of pressurized gas as the propulsion force for liquid atomization. An ultrasonic nebulizer uses power introduced by a piezoelectric element in a liquid reservoir to convert the liquid into breathable 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 this 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] "Median Mass Diameter" or "MMD" is determined by laser diffraction or impactor measurement and is the average particle size based on mass.

[0035]

[0042] The "aerodynamic median 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 velocity is 28 liters per minute according to the Andersen Cascade Impactor (ACI) and 15 liters per minute according to the Next Generation Impactor (NGI). The "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, and currently, there are limited effective treatments, with no approved therapies. The prevalence of NTM disease is reported to be increasing, and according to the American Thoracic Society, it is thought to be higher than the prevalence of tuberculosis in the United States. According to the National Center for Biotechnology Information, epidemiological studies indicate that the presence of NTM infection is increasing in developing countries, possibly due to the introduction of tap water. Women with characteristic phenotypes are considered to be at higher risk of acquiring NTM infection, along with patients with abnormalities in cystic fibrosis membrane conductance regulators. In general, high-risk groups for increased morbidity and mortality with NTM lung disease are those with cavitary lesions, low BMI, older age, and a high comorbidity index.

[0037]

[0044] NTM lung disease is often a chronic condition characterized by bronchiectasis and cavitation, leading to progressive inflammation and lung damage. NTM infections often require long-term hospitalization for medical management. Treatment typically involves multi-drug regimens, which may be poorly tolerated and have limited efficacy, especially in patients with severe disease or those who have failed previous treatment attempts. According to a company-provided 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] The management of lung disease caused by nontuberculous mycobacteria (NTM) infections involves long-term, multi-drug regimens, which are often associated with drug toxicity and suboptimal outcomes. Achieving NTM culture negativity is one of the treatment goals and represents the clinically most important microbiological endpoint in patients with NTM lung infections.

[0039]

[0046] In one embodiment, the present invention provides a method for treating non-tuberculous mycobacterial (NTM) lung infection in a patient requiring such treatment. The method in one embodiment comprises administering to a patient for a period of time a composition comprising a liposomal complexed aminoglycoside or a pharmaceutically acceptable salt thereof. In one embodiment, the liposomal 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 neutral lipids. In one embodiment, the neutral lipids comprise phospholipids and sterols. In a further embodiment, the phospholipid is phosphatidylcholine. In a further embodiment, the phosphatidylcholine is dipalmitoylphosphatidylcholine (DPPC). In a further embodiment, the sterol is cholesterol. In one embodiment, the non-tuberculous mycobacterial lung infection is a refractory non-tuberculous mycobacterial lung infection. In one embodiment, patients show an increase in the number of meters walked in a 6MWT and / or negative conversion of NTM cultures during or after the administration period compared to pre-treatment.

[0040]

[0047] A therapeutic response can be any response that the user (e.g., a clinician) recognizes as an effective response to treatment. Generally, a therapeutic response is a reduction, inhibition, delay, or prevention of the growth or reproduction of one or more NTMs, or the death of one or more NTMs. A therapeutic response may also be reflected in improvements in lung function, such as forced expiratory volume in one second (FEV1). In one embodiment where a patient is treated for an NTM lung infection, the therapeutic response is measured as a change from baseline in a complete semi-quantitative measure of mycobacterial culture or an improvement in walking distance in a 6-minute walk test (6MWT). Furthermore, determining the appropriate duration of treatment, appropriate dose, and any possible concomitant therapies based on the assessment of the therapeutic response is within the scope of the skills of those skilled in the art.

[0041]

[0048] NTM lung 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. 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 The affected bacteria are M. avium 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, nontuberculous mycobacterial lung infection is M. avium complex (MAC) (M. avium and M. intracellulare), M. abscessus, or M. avium. In a further embodiment, M. avium infection is M. avium subsp. hominissuis. In one embodiment, nontuberculous mycobacterial lung infection is M. avium complex (MAC) (M. avium and M. intracellulare). In another embodiment, NTM lung infection is refractory nontuberculous mycobacterial lung infection.

[0042]

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

[0044]

[0051] In one embodiment, NTM pulmonary infection is accompanied by cavitary lesions. In one embodiment, NTM pulmonary infection is a nodular infection. In a further embodiment, NTM pulmonary infection is a nodular infection with minute cavitary lesions.

[0045]

[0052] In one embodiment, the aminoglycoside or a pharmaceutically acceptable salt thereof administered via the method described herein is selected from amikacin, apramycin, arbekacin, astromycin, capreomycin, dibekacin, flamycetin, gentamicin, hygromycin B, isepamycin, kanamycin, neomycin, netylmycin, paromomycin, rhodostreptomycin, ribostamycin, shisomycin, spectinomycin, streptomycin, tobramycin, verdamycin, or a pharmaceutically acceptable salt thereof. In a further embodiment, the aminoglycoside is amikacin. In yet another embodiment, the amikacin is amikacin sulfate. In yet another embodiment, the aminoglycoside is selected from the aminoglycosides, pharmaceutically acceptable salts thereof, or combinations thereof shown in Table 2 below. For example, one or more pharmaceutically acceptable salts, such as sulfates, of the aminoglycosides shown in Table 2 can be formulated into liposome compositions and administered to patients requiring treatment for NTM, for example, via nebulizer-based lung delivery.

[0046] [Table 2]

[0047]

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

[0048]

[0054] In one embodiment, the aminoglycoside is an aminoglycoside free base or a salt thereof, a solvate, or other non-covalent derivative. 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, unless otherwise noted, the present invention includes each of its own racemic compounds and each of its own non-racemic compounds. Where the activator has an unsaturated carbon-carbon double bond, both cis (Z) and trans (E) isomers are within the scope of the present invention. Where the activator exists in tautomers such as keto-enol tautomers, each tautomer is intended to be included within the present invention. In one embodiment, amikacin exists in the pharmaceutical composition as an amikacin base or 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 embodiment, the present invention provides a method for treating or preventing NTM lung infection. Treatment is achieved by delivery of the composition by inhalation via atomization of the composition comprising a liposomal aminoglycoside composition. In one embodiment, the composition comprises an aminoglycoside encapsulated in a plurality of liposomes, for example, an aminoglycoside selected from one or more of the aminoglycosides in Table 1 and / or 2, or a pharmaceutically acceptable salt thereof.

[0050]

[0056] The pharmaceutical compositions provided herein are liposome-complexed aminoglycosides, for example, liposome dispersions containing aminoglycosides encapsulated in a plurality of liposomes. The pharmaceutical compositions are dispersions containing "liposome-complexed aminoglycosides" or "aminoglycosides encapsulated in liposomes." "Liposome-complexed aminoglycosides" include embodiments in which aminoglycosides (or combinations of aminoglycosides) are encapsulated in liposomes, and include any form of aminoglycoside composition in which at least about 1% by weight of aminoglycosides associates with liposomes as part of a complex with liposomes, or as liposomes in which the aminoglycosides may be in an aqueous phase, a hydrophobic bilayer phase, or the interface head region of the liposome bilayer.

[0051]

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

[0052]

[0058] As defined above, embodiments of liposome-complexed aminoglycosides include embodiments in which an aminoglycoside or a pharmaceutically acceptable salt thereof is encapsulated in a plurality of liposomes. Furthermore, liposome-complexed aminoglycosides represent any composition, solution, or suspension in which at least about 1% by weight of an aminoglycoside is associated with a lipid, either as part of a complex with liposomes, or as a liposome in which the aminoglycoside may be in an aqueous phase, a hydrophobic bilayer phase, or the interface head region of the liposome bilayer. In one embodiment, prior to atomization, 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 thus associated. In one embodiment, the association is measured by filtration separation in which the lipid and the lipid-associated drug are retained (i.e., in the retained substance) and the free drug is in the filtrate.

[0053]

[0059] The method provided herein involves administering to a patient in need 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, one or more lipids are synthetic, semi-synthetic, or native 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 consists of electrically neutral lipids. In a further embodiment, the lipid component includes DPPC and cholesterol.

[0054]

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

[0055]

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

[0056]

[0062] Other examples of lipids for use by 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), dioleylphosphatidylethanolamine (DOPE), palmitoylstearoylphosphatidylcholine (PSPC), and monoacylated phospholipids, such as mono-oleoylphosphatidylethanolamine (MOPE).

[0057]

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

[0058]

[0064] In one embodiment, at least one cationic lipid (positively charged lipid) is provided in the lipid components of a plurality of liposomes present in the liposomal aminoglycoside composition described herein for use in a method for treating NTM lung infection in patients requiring such treatment. Cationic lipids suitable for use according to the present invention include, but are not limited to, ammonium salts of fatty acids, phospholipids, and glycerides. Fatty acids include fatty acids with a carbon chain length of 12 to 26 carbon atoms, which are saturated or unsaturated. Some specific examples include, but are not limited to, myristylamine, palmitylamine, laurylamine and stearylamine, dilauroylethyl phosphocholine (DLEP), dimyristoylethyl phosphocholine (DMEP), dipalmitoylethyl phosphocholine (DPEP) and distearoylethyl phosphocholine (DSEP), N-(2,3-di-(9-(Z)-octadecenyloxy)-propa-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 a plurality of liposomes present in the liposomal aminoglycoside composition described herein for use in a method of treating NTM lung infection in patients requiring such treatment. Possible negatively charged lipids include phosphatidyl glycerol (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] While we do not wish to be bound by theory, phosphatidylcholines such as DPPC assist the uptake of aminoglycoside agonists by cells in the lungs (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 the persistence of the active properties of the inhaled composition and in the transport of the composition across the lungs (transcytosis) for systemic uptake, in addition to reducing particle aggregation. While we do not wish to be bound by theory, sterol compounds are thought to affect the release properties of the composition.

[0061]

[0067] Liposomes are completely closed lipid bilayer membranes that contain a certain volume of trapped water. Liposomes can be monolayer vesicles (having a single membrane bilayer), multilayer vesicles (an onion-like structure characterized by multiple membrane bilayers, each separated from its neighbor by an aqueous layer), or a combination thereof. The bilayer consists of two lipid monolayers, each having a hydrophobic "tail" region and a hydrophilic "head" region. The structure of the membrane bilayer is such that the hydrophobic (nonpolar) "tail" of the lipid monolayer faces the center of the bilayer, while the hydrophilic "head" faces the aqueous phase.

[0062]

[0068] In one embodiment, the weight ratio of lipids to aminoglycosides (hereinafter also referred to as “lipid:aminoglycoside”) in the pharmaceutical compositions provided herein 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 (lipid to aminoglycoside weight ratio) is approximately 0.10:1.0 to approximately 1.25:1.0, approximately 0.25:1.0 to approximately 1.25:1.0, approximately 0.50:1.0 to approximately 1.25:1.0, or approximately 0.6:1 to approximately 1.25:1.0. In another embodiment, the lipid to aminoglycoside weight ratio is approximately 0.1:1.0 to approximately 1.0:1.0, or approximately 0.25:1.0 to approximately 1.0:1.0, or approximately 0.5:1 to 1:1.0.

[0063]

[0069] In another embodiment, 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 a further embodiment, the lipid-to-aminoglycoside weight ratio is about 0.7:1.0 or less or about 0.7:1.0. In yet another embodiment, the lipid-to-aminoglycoside weight ratio is about 0.5:1.0 to about 0.8:1.0.

[0064]

[0070] To minimize the volume of administration and reduce the number of doses given to the patient, in one embodiment, it is important that the liposome capture of the aminoglycoside (e.g., amikacin, which is an aminoglycoside) is highly efficient, and that the liposomes be kept small enough to permeate the patient's mucosa and biological membranes, while the lipid-to-aminoglycoside weight ratio is as low as possible and / or practical. In one embodiment, the L-aminoglycoside weight ratio in the compositions provided herein, i.e., compositions 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 further embodiments, the liposomes provided herein are small enough to effectively permeate bacterial biological membranes. In further embodiments, the average diameter of multiple liposomes measured by light scattering is approximately 200 nm to 400 nm, or approximately 250 nm to 400 nm, or approximately 250 nm to 300 nm, or approximately 200 nm to 300 nm. In further embodiments, the average diameter of multiple liposomes measured by light scattering is approximately 260 nm to 280 nm.

[0065]

[0071] In one embodiment, the liposome compositions described herein are prepared by one of the methods described in U.S. Patent Application Publication 2013 / 0330400 or U.S. Patent No. 7,718,189, each of which is incorporated by reference in any way. Liposomes can be prepared by various methods (see, for example, Cullis et al. (1987)). In one embodiment, one or more of the methods described in U.S. Patent Application Publication 2008 / 0089927 are used herein to prepare an aminoglycoside-encapsulated lipid composition (liposome dispersion). The disclosures of U.S. Patent Application Publication 2008 / 0089927 are incorporated by reference in any way. 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 may be produced before, during, or after mixing with the lipid. Furthermore, the coacervate can be an activator coacervate.

[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 aminoglycosides with the lipid solution. In a further embodiment, the organic solvent is ethanol. In a further embodiment, the lipid solution includes phospholipids and sterols, such as DPPC and cholesterol.

[0067]

[0073] In one embodiment, liposomes are prepared by sonication, injection, homogenization, swelling, electroformation, inverted emulsion, or reverse-phase evaporation. Bangham's method (J. Mol. Biol. (1965)) prepares conventional multi-membrane vesicles (MLVs). Lenk et al. (US Patents 4,522,803, 5,030,453, and 5,169,637), Fountain et al. (US Patents 4,588,578), and Cullis et al. (US Patents 4,975,282) disclose methods for preparing multi-membrane liposomes having substantially equal interphase solute distributions in each of their aqueous compartments. Paphadjopoulos et al. (US Patent 4,235,871) disclose the preparation of oligolamellar liposomes by reverse-phase evaporation. Each method is suitable for use according to the present invention.

[0068]

[0074] Monolayer vesicles can be fabricated from MLVs by several techniques, e.g., injection techniques as described in U.S. Patent No. 5,008,050 and U.S. Patent No. 5,059,421. Sonication and homogenization may be used to fabricate smaller monolayer liposomes from larger liposomes (see, e.g., Paphadjopoulos et al. (1968); Deamer and Uster (1983); and Chapman et al. (1968)).

[0069]

[0075] The liposome preparation by Bangham et al. (J. Mol. Biol. 13, 1965, pp. 238-252) involves suspending phospholipids in an organic solvent, then evaporating it to dryness, leaving a phospholipid film in the reaction vessel. Next, an appropriate amount of aqueous phase is added, causing the mixture to "swell," and the resulting liposomes, consisting of multilayer vesicles (MLVs), are dispersed by mechanical means. This preparation provides the basis for the generation of small, sonicated single-layer vesicles and large single-layer vesicles, as 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 producing large single-layer vesicles (LUVs), such as reverse-phase evaporation, injection, and surfactant dilution, may be used. A review of these and other methods for preparing liposomes can be found in the text, Liposomes, edited by Marc Ostro, Marcel Dekker, Inc., New York, 1983, Chapter 1, which is incorporated herein by reference. Similarly, for all purposes, see also Szoka, Jr. et al. (Ann. Rev. Biophys. Bioeng. 9, 1980, p. 467), which is incorporated herein by reference in its entirety.

[0071]

[0077] Other techniques for producing liposomes include those that produce reverse-phase evaporative vesicles (REVs), U.S. Patent No. 4,235,871. Another class of liposomes that can be used is characterized by having substantially equal lamellar solute distributions. This class of liposomes is named stable plurilamellar vesicles (SPLVs), as defined in U.S. Patent No. 4,522,803, and includes single-phase vesicles described in U.S. Patent No. 4,588,578 and the above-mentioned freeze-thawed multi-layer vesicles (FATMLVs).

[0072]

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

[0073]

[0079] In one embodiment, the pharmaceutical composition contains liposomes having an average diameter of approximately 0.01 to approximately 3.0 microns, for example, in the range of approximately 0.2 to approximately 1.0 microns, as measured by light scattering before atomization. In one embodiment, the average diameter of the liposomes in the composition is approximately 200 nm to approximately 300 nm, approximately 210 nm to approximately 290 nm, approximately 220 nm to approximately 280 nm, approximately 230 nm to approximately 280 nm, approximately 240 nm to approximately 280 nm, approximately 250 nm to approximately 280 nm, or approximately 260 nm to approximately 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 method described herein involves administering a liposome-conjugated aminoglycoside composition, such as a liposome-conjugated amikacin (e.g., amikacin sulfate) composition, to a patient in need, via inhalation, for example, 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, provided in 8 mL of the composition. In one embodiment, the amount of aminoglycoside administered to the subject is about 590 mg, provided in 8 mL of composition. In another embodiment, the amount of aminoglycoside administered to the subject is about 600 mg, provided in 8 mL of 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 yet 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 another embodiment, the aminoglycoside is amikacin, and the amount of amikacin administered to the subject is about 560 mg, provided in 8 mL of composition. In one embodiment, the aminoglycoside is amikacin, and the amount of amikacin administered to the subject is 590 mg, provided in an 8 mL composition. In another embodiment, the aminoglycoside is amikacin, and the amount of aminoglycoside administered to the subject is approximately 600 mg, provided in an 8 mL composition.

[0075]

[0081] In one embodiment, the method described herein is carried out by using a system comprising a liposome-conjugated aminoglycoside composition, for example, a liposome-encapsulated amikacin composition (e.g., amikacin sulfate) and a nebulizer. In one embodiment, the liposome-conjugated 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, for example, amikacin 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 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 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 twice daily.

[0077]

[0083] A method provided herein, in one embodiment, involves administering one of the compositions described herein (e.g., via a nebulizer) to a patient in need for a period of administration including at least one, two, three, four, five, or six months. In one embodiment, the period of administration is followed by a period in which no composition is administered (referred to as an "off period"), followed by another period of administration. In one embodiment, the off period is about one, two, three, four, five, or six months.

[0078]

[0084] In one embodiment, the administration period is approximately 15 to 400 days, for example, approximately 45 to 300 days, or approximately 45 to 270 days, or approximately 80 to 200 days. In one embodiment, the administration period includes administering the composition to a patient in need in a once-daily medication session.

[0079]

[0085] In another embodiment, the NTM treatment method described herein includes administering a liposome-conjugated aminoglycoside composition to a patient in need via once-daily dosing sessions during a treatment period. In a further embodiment, the treatment period is about 15 to about 275 days, or about 20 to 235 days, or about 28 to about 150 days. For example, the method provided herein includes administering an aminoglycoside composition to a patient in need once daily in a single dosing session during a treatment period of about 15 to about 300 days, or about 15 to about 250 days, or about 15 to about 200 days, or about 15 to about 150 days, or about 15 to about 125 days, or about 15 to about 100 days. In another embodiment, the treatment period is about 50 to about 200 days. During the administration period, in one embodiment, patients requiring it are administered the aminoglycoside composition via spraying, with approximately 500 mg to 1000 mg of aminoglycoside, for example, approximately 500 mg to 700 mg of aminoglycoside (for example, approximately 590 mg of aminoglycoside), administered daily in a single dosing session.

[0080]

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

[0081]

[0087] In one embodiment, a patient requiring it is administered a liposome-encompassed aminoglycoside composition in a treatment cycle that includes an administration period and an off period. In a further embodiment, the treatment cycle is practiced 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 lung infection are provided in Table 3 below. However, in another embodiment, the method provided herein does not include an off-period, but instead includes only the administration period. In a further embodiment, one of the administration periods shown in Table 3 is used in the method provided herein. In a further embodiment, the patient is administered a liposomal aminoglycoside composition once daily during the administration period in a single medication session.

[0083] [Table 3-1]

[0084] [Table 3-2]

[0085]

[0089] In one embodiment, the system provided herein comprises about 8 mL of liposomal amikacin composition and a nebulizer. In one embodiment, the density of the liposomal amikacin composition is about 1.05 g / mL; in one embodiment, about 8.4 g of 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 requiring it.

[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 the composition provided in Table 4 below.

[0087] [Table 4]

[0088]

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

[0089]

[0092] As provided throughout, the method described herein involves administering an effective amount of a liposomal aminoglycoside composition to a patient requiring treatment for NTM lung infection via inhalation. In one embodiment, inhalation delivery is carried out 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 includes 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, a method for treating NTM infection is provided by administering a liposome-conjugated aminoglycoside composition to a patient in need via a nebulizer during a once-daily dosing session. In a further embodiment, the aminoglycoside is amikacin, for example, amikacin sulfate. In a further embodiment, the lipid component of the liposome comprises DPPC and cholesterol. In a further embodiment, the nebulizer is one of those described in U.S. Patent Application Publication No. 2013 / 0330400, which is incorporated herein by reference in whole for all purposes.

[0092]

[0095] The operating principle of a pneumatic nebulizer is generally known to those skilled in the art and is described, for example, in Respiratory Care, Vol. 45, No. 6, pp. 609-622 (2000). Briefly, the supply of pressurized gas is used as the propulsion for atomizing a liquid in a pneumatic nebulizer. Compressed gas is delivered, which creates a negative pressure region. The solution to be aerosolized is then delivered into the gas stream and sheared to form a liquid film. This film is unstable and breaks due to surface tension to form droplets. Smaller particles, i.e., particles having the above-mentioned MMAD and FPF properties, can then be formed by placing a barrier wall in the aerosol stream. In one embodiment of the pneumatic nebulizer, the gas and solution are mixed before they exit the outlet port (nozzle) and interact with the barrier wall. In another embodiment, mixing does not occur until the liquid and gas exit the outlet port (nozzle). In one embodiment, the gas is air, O2 and / or CO2.

[0093]

[0096] In one embodiment, droplet size and discharge rate can be adjusted in a pneumatic nebulizer. However, it should be considered whether the composition being atomized and the properties of the composition (e.g., %) of associated aminoglycosides are modified by improvements to the nebulizer. For example, in one embodiment, the gas velocity and / or the velocity of the pharmaceutical composition are modified to achieve the discharge rate and droplet size of the present invention. In addition to or instead of this, the flow rate of the gas and / or solution may be adjusted to achieve the droplet size and discharge rate of the present invention. For example, in one embodiment, increasing the gas velocity reduced the droplet size. In one embodiment, the ratio of pharmaceutical composition flow to gas flow is adjusted to achieve the droplet size and discharge rate of the present invention. In one embodiment, increasing the ratio of liquid to gas flow increased the particle size.

[0094]

[0097] In one embodiment, the discharge rate of a pneumatic nebulizer is increased by increasing the filling volume of the liquid reservoir. While we do not wish to be bound by theory, the increase in discharge rate may be due to a reduction in dead volume within the nebulizer. In one embodiment, the atomization time is reduced by increasing the flow rate 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 liquid storage bag is used to capture the aerosol during the atomization process, and the aerosol is then delivered to the subject via inhalation. In another embodiment, the nebulizer provided herein includes a valved open-port design. In this embodiment, the nebulizer discharge increases as the patient inhales through the nebulizer. During the exhalation phase, a one-way valve redirects the 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 drug dose. Rather, the nebulizer has a maximum 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 produce 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 located at the rear of the mixing chamber and carries the aerosol through the mouthpiece to the patient. During exhalation, 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 during the next breath, and this cycle continues until the drug reservoir of the nebulizer is empty.

[0098]

[0101] In one embodiment, the effective atomization time 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 effective atomization time of the aminoglycoside composition provided herein is less than 15 minutes or less than 13 minutes. In one embodiment, the effective atomization time of the aminoglycoside composition provided herein is about 13 minutes.

[0099]

[0102] In one embodiment, the composition described herein is administered once daily to a patient in need.

[0100]

[0103] In another embodiment, a patient is treated for NTM lung infection by one of the methods and / or compositions provided herein. In a further embodiment, the composition comprises a liposomal amikacin composition. In a further embodiment, the composition comprises about 500 mg to about 600 mg of amikacin, DPPC and cholesterol, and the lipid-to-aminoglycoside weight ratio of the composition is 0.75:1.0 or less, for example, 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 unresponsive 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, before atomization of the aminoglycoside composition, about 70% to about 100% of the aminoglycosides present in the composition are liposome-conjugated. In a further embodiment, the aminoglycoside is an aminoglycoside. In a further embodiment, the aminoglycoside is amikacin. In another embodiment, before atomization, 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 aminoglycosides present in the composition are liposome-conjugated. In a further embodiment, the aminoglycoside is amikacin or tobramycin. In a further embodiment, the aminoglycoside is amikacin. In another embodiment, before atomization, about 98% of the aminoglycosides present in the composition are liposome-conjugated. In a further embodiment, the aminoglycoside is amikacin or tobramycin. In further embodiments, the aminoglycoside is amikacin (e.g., amikacin sulfate).

[0103]

[0106] In one embodiment, during atomization, approximately 20% to 50% of the liposome-conjugated aminoglycoside is released due to shear stress on the liposomes. In a further embodiment, the aminoglycoside is amikacin. In another embodiment, during atomization, approximately 25% to 45% or approximately 30% to 40% of the liposome-conjugated aminoglycoside is released from the liposome complex due to shear stress on the liposomes. In a further embodiment, the aminoglycoside is amikacin. In a further embodiment, amikacin is amikacin sulfate.

[0104]

[0107] When the compositions described herein are atomized for administration to patients requiring treatment for NTM infection, an aerosolized composition is produced, and in one embodiment, the aerodynamic median diameter (MMAD) of the aerosolized composition is about 1.0 μm to about 4.2 μm, as measured by an Andersen cascade impactor (ACI). In one embodiment, the MMAD of the aerosolized composition is about 3.2 μm to about 4.2 μm, as measured by an ACI. In one embodiment, the MMAD of the aerosolized composition is about 1.0 μm to about 4.9 μm, as measured by a next-generation impactor (NGI). In a further embodiment, the MMAD of the aerosolized composition is about 4.4 μm to about 4.9 μm, as measured by an NGI.

[0105]

[0108] In one embodiment, the particulate matter (FPF) of the aerosolized composition is approximately 64% or more, as measured by an Andersen Cascade Impactor (ACI), or approximately 51% or more, as measured by a Next-Generation Impactor (NGI). In another embodiment, the FPF of the aerosolized composition is approximately 70% or more, as measured by ACI, approximately 51% or more, as measured by NGI, or approximately 60% or more, as measured by NGI.

[0106]

[0109] During atomization, liposomes in the pharmaceutical composition release the drug. In one embodiment, the amount of liposome-complexed aminoglycosides after atomization is about 45% to about 85%, or about 50% to about 80%, or about 51% to about 77%. In this specification, these percentages are also referred to as “associated aminoglycoside percentage after atomization.” As provided herein, in one embodiment, the liposomes contain an aminoglycoside, for example, amikacin. In one embodiment, the associated aminoglycoside percentage after atomization is about 60% to about 70%. In a further embodiment, the aminoglycoside is amikacin. In another embodiment, the associated aminoglycoside percentage after atomization is about 67%, or about 65% to 70%. In a further embodiment, the aminoglycoside is amikacin. In a further embodiment, amikacin is amikacin sulfate.

[0107]

[0110] In one embodiment, an aerosol is recovered from the air by condensation in a cold trap, and then the percentage of associated aminoglycosides after atomization is measured by assaying the liquid for the freed and encapsulated aminoglycosides (associated aminoglycosides).

[0108]

[0111] In another embodiment, the method provided herein is practiced for the treatment or prevention of one or more NTM lung infections in patients with cystic fibrosis. In a further embodiment, the composition administered to a patient in need of treatment is one of the compositions shown in Table 4 above.

[0109]

[0112] In one embodiment, the patient requiring treatment for 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 related to CF in the patient requiring treatment.

[0110]

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

[0111]

[0114] In one embodiment, patients requiring treatment by one of the methods described herein are patients with cystic fibrosis, bronchiectasis, ciliary dysfunction, chronic smokers, patients with chronic obstructive pulmonary disease (COPD), or patients who have previously been unresponsive to treatment. In another embodiment, a patient with cystic fibrosis is treated for an NTM lung infection by one of the methods provided herein. In yet another embodiment, the patient is a patient with bronchiectasis, a patient with COPD, or a patient with asthma. 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, patients subjected to the methods described herein have concomitant conditions. For example, in one embodiment, a patient requiring treatment with one of the methods described herein has, in addition to NTM pulmonary infection, diabetes, mitral valve disorder (e.g., mitral valve prolapse), acute bronchitis, pulmonary hypertension, pneumonia, asthma, tracheal cancer, bronchial cancer, lung cancer, cystic fibrosis, pulmonary fibrosis, pharyngeal abnormalities, tracheal abnormalities, bronchial abnormalities, aspergillosis, HIV, or bronchiectasis.

[0113]

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

[0114]

[0117] In some embodiments, patients experience an improvement in lung function compared to their pre-treatment FEV1 for at least 15 days after the end of the administration period. For example, patients may experience an increase in FEV1, an increase in blood oxygen saturation, or both. In some embodiments, patients have an FEV1 that is at least 5% higher than their pre-administration FEV1 (after the administration period or treatment cycle). In other embodiments, FEV1 increases by 5-50% compared to their pre-administration FEV1. In other embodiments, FEV1 increases by 25-500 mL compared to their pre-administration FEV1. In some embodiments, blood oxygen saturation increases by at least 1% compared to their pre-administration oxygen saturation.

[0115]

[0118] In one embodiment, a 6-minute walk test (6MWT) is used to evaluate the effectiveness of the treatment method provided herein. The 6MWT is a practical and simple test used for the objective assessment of functional motor ability, measuring the distance a patient can walk in 6 minutes (for all purposes, the entire text is incorporated herein by reference; see American Thoracic Society. (2002). Am J Respir Crit Care Med. 166, pp. 111–117).

[0116]

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

[0117]

[0120] In another embodiment, patients subjected to one of the NTM methods described herein exhibit a greater number of meters walked in a 6MWT compared to patients receiving non-liposomal aminoglycoside therapy. In one embodiment, the greater number of meters walked in a 6MWT compared to patients receiving non-liposomal aminoglycoside therapy 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. In another embodiment, the greater number of meters walked in a 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 distance walked in a larger 6MWT was approximately 5 to 80 meters, or approximately 5 to 70 meters, or approximately 5 to 60 meters, or approximately 5 to 50 meters.

[0118]

[0121] In one embodiment, the liposomal aminoglycoside composition provided herein is administered to a patient requiring treatment for NTM lung disease in conjunction with additional therapeutic agents.

[0119]

[0122] In one embodiment, the liposomal aminoglycoside composition provided herein is administered to a patient requiring treatment for NTM lung disease together 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 by inhalation.

[0120]

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

[0121]

[0124] In one embodiment, one or more additional therapeutic agents are macrolide antibiotics, 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 composition provided herein is administered to a patient requiring treatment for NTM lung disease together with one or more additional therapeutic agents, one or more of which are rifamycin compounds. In a further embodiment, rifamycin is rifampin. In another embodiment, rifamycin is rifabutin, rifapentin, rifaximin, or a combination thereof.

[0123]

[0126] In a further embodiment, one or more additional therapeutic agents are quinolones. 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 requiring NTM treatment, and the second therapeutic agent is a second aminoglycoside. In a further embodiment, the second aminoglycoside is amikacin, apramycin, arbekacin, astromycin, bekanamycin, voformycin, bruramycin, capreomycin, dibekacin, dactymycin, ethymicin, flamycetin, gentamicin, H107, hygromycin, hygromycin B, inosamycin, K-4619, isepamycin, KA-5685, kanamycin, neomycin, netylmycin, paromomycin, prazomycin, ribostamycin, shisomycin, rhodostreptomycin, sorbisin, spectinomycin, sporalycin, streptomycin, tobramycin, verdamycin, vertilmycin, pharmaceutically acceptable salts thereof, or combinations thereof. In a further embodiment, the second aminoglycoside is administered intravenously or by inhalation. In one embodiment, the second aminoglycoside is streptomycin.

[0125]

[0128] In another embodiment, the liposomal aminoglycoside compositions provided herein are administered to patients requiring treatment for NTM lung disease together with one or more additional therapeutic agents, the one or more additional therapeutic agents being ethambutol, isoniazid, cefoxitine, or imipenem. [Examples]

[0126]

[0129] The present invention will be further illustrated by reference to the following embodiments. However, as with the embodiments described above, it should be noted that these embodiments are illustrative and should not be construed as limiting the scope of the present invention.

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

[0130] The increasing prevalence of NTM-LD is a public health concern, 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 an amikacin-releasing lipid composition under development for the treatment of patients with refractory NTM lung disease. This study evaluated the efficacy, safety, and tolerability of LAI in patients in a randomized, double-blind (DB) trial conducted at 19 sites in North America. Figure 1 is a flowchart illustrating the trial design, and Figure 2 shows the patient distribution for this trial.

[0128]

[0131] The LAI composition contained the following components.

[0129] [Table 5]

[0130]

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

[0131]

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

[0132]

[0134] Of the 136 patients screened, 90 were randomized (CF 19%; non-CF 81%; 64% with MAC and 36% with M. abscessus). 54% of patients were over 60 years old; 31% were between 40 and 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] The trial will be completed when 80 and 59 patients complete the DB and OL phases, respectively. Demographic 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 had the following characteristics: (1) concomitant lung disease, with 17 patients having cystic fibrosis; (2) mean age 59 years, including young cystic fibrosis patients; (3) lung abnormalities, including 68 patients with cavitary lesions and 21 patients with nodular disease, further including minor cavitary lesions; (4) mean BMI of 21.98, compared to corresponding CDC data collected between 2007 and 2010, which revealed the mean US body mass index (BMI) to be 28.6 for adult males and 28.7 for adult females; and (5) mean baseline of approximately 441m for all patients, with both arms having approximately the same mean 6-minute walk distance.

[0136]

[0137] Sputum, smear status, signs / symptoms, occurrence of lung exacerbations, rescue of antimycobacterial drugs, 6-minute walk distance (6MWD), chest computed tomography, spirometry, clinical / laboratory safety parameters, and quality of life were assessed every 28 days. The primary endpoint for mycobacterial cultures was the change from baseline on a semi-quantitative scale; the secondary endpoint was the proportion of patients whose NTM cultures became negative at day 84 for LAI vs. placebo. All patients visited the hospital for safety follow-up 28 days after the last dose of the study drug, and up to day 196 for patients in the OL phase.

[0137]

[0138] Figure 4 is a graph showing the mean change from baseline in a fully semi-quantitative measure of mycobacterial culture (mITT population) as a function of trial day in both the double-blind and open-label phases of the study. As shown in the figure, patients treated with LAI showed at least one-step reduction in the treatment arm versus the placebo arm during the double-blind phase.

[0138]

[0139] Tables 6-8 summarize the proportion of patients (mITT population) with negative sputum culture for NTM at days 84 and 168 in each subgroup of the treatment arm. Statistically significant intergroup differences for LAI vs. placebo were observed in patients with non-CF infection (P=.01), MAC infection (P=.017), female (P=.004), Caucasian (P=.031), and under 63 years of age (P=.041) in patients achieving negative sputum culture for NTM at day 84 (Table 6).

[0139]

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

[0140]

[0141] The time to culture conversion was statistically significantly higher in the LAI arm patients who achieved culture-negative results at all visits during the double-blind phase (days 28, 56, and 84) (Figure 5, top). Specifically, LAI achieved statistical significance in achieving negative culture at day 84, with 11 out of 44 LAI patients compared to 3 out of 45 placebo patients (P=.01) (Figure 5, top). Compared to placebo, LAI achieved statistical significance in the proportion of patients with MAC infection who achieved culture-negative results 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).

[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 shown in Figure 6.

[0142] [Table 7]

[0143] [Table 8]

[0144] [Table 9]

[0145]

[0143] The 6-minute walk test (6MWT) evaluated the effect of LAI on overall physical function or ability. Results for the 6MWT endpoint (change from baseline from day 1 to the final day 84 of the double-blind trial) are provided in Figures 7 and 8. LAI demonstrated statistical significance of the 6MWT in the double-blind phase (LAI vs. placebo: 23.895 vs. -25.032 meters, P=0.009). The mean change in walking distance (meters) in the 6MWT from baseline to day 84 was significantly higher in patients receiving LAI compared to placebo (20.64 m vs. -25.03 m) (Figure 7, bottom). In the open-label phase, patients with the LAI arm continued to improve in the 6MWT, while patients in the placebo group who started LAI showed a dramatic decrease in the rate of deterioration (Figures 7 and 8). Furthermore, in patients who remained culture-negative until the end of the open-label phase, there was a significant difference in the mean change in the 6MWT score from baseline to day 168 compared to patients who did not remain culture-negative (55.75m vs. -13.42m) (Figure 8, bottom).

[0146]

[0144] Patients with treatment-refractory NTM pulmonary infection showed improved walking distance in the 6MWT when LAI was added to their guideline-based treatment background. Patients who remained culture-negative throughout the study achieved better physical functioning capacity as assessed by the 6MWT.

[0147]

[0145] The sample population enrolled in the mITT trial showed the following regarding culture transformation, measured as three consecutive negative sputum cultures before day 168: (1) A total of 16 patients, all of whom had non-cystic fibrosis, showed culture transformation; (2) 15 patients had MAC and 1 had M. abscessus; (3) 8 patients did not show treatment success despite more than 24 months of non-LAI treatment, 4 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) It did not show success; (5) Seven patients showed nodular disease, two patients showed nodular disease and small cavitary lesions, and seven patients showed cavitary lesions; (6) Eleven patients initiated transformation on or before day 56 after the initiation of LAI treatment, two patients transformed on day 84 after the initiation of LAI treatment, and three patients transformed on day 112 after the initiation of LAI treatment; and (7) The 6MWT for transformed patients (n=16) versus non-transformed patients (n=43) at day 168 had a p-value of 0.0034, with 89.34 meters (transformed patients) versus 3.85 meters (non-transformed patients).

[0148]

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

[0149]

[0147] Furthermore, patients who transitioned from LAI in the double-blind phase to the open-label phase (see Figure 1 for study design) were found to continue improving. In addition, patients who transitioned from placebo to the open-label phase showed a dramatic reduction in their rate of decline. Most treatment-related adverse events (TEAEs) were mild or moderate in severity, and the majority of TEAEs were virtually respiratory (Table 9). Local events and exacerbations of underlying lung disease infection were the most common TEAEs. A small number of patients discontinued the study drug due to these events.

[0150] [Table 10]

[0151] Example 2: Testing of inhaled liposomal amikacin (LAI) in patients with non-CF M.avium complex (MAC) lung infection

[0148] LAI (also referred to herein as "Arikayce®" or "ARIKAYCE®") is an amikacin-releasing lipid composition under 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) lung infection. Figure 9 is a flowchart of the study design.

[0152]

[0149] LAI composition contains the following components:

[0153] [Table 11]

[0154]

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

[0155] [Table 12]

[0156]

[0151] Patients will be randomized in a 2:1 ratio into two groups: (i) LAI 590 mg + basal therapy and (ii) basal therapy only. Each patient group will receive daily medication for 8 months. Primary culture transformation will be evaluated at 6 months. A 6MWT will also be performed for each patient at 6 months.

[0157]

[0152] Cultured individuals will continue treatment for 12 months after transformation.

[0158]

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

[0159]

[0154] The embodiments illustrated and discussed herein are intended solely to teach those skilled in the art the best methods known to the inventors for constructing and using the present invention. As will be apparent to those skilled in the art in light of the foregoing teaching, improvements and modifications of the above embodiments of the present invention are possible without departing from the present invention. Thus it will be understood that within the scope of the claims and their equivalents the present invention may be carried out in ways other than those specifically described. Accordingly, the foregoing description and drawings are merely examples, and the disclosure is described in more detail by the following claims.

Claims

1. A pharmaceutical composition for treating Mycobacterium avium complex (MAC) pulmonary infection in patients requiring treatment, which is used in combination with a macrolide antibiotic, a rifamycin compound, and ethambutol. The aforementioned patient has non-cystic fibrosis underlying lung disease, The pharmaceutical composition comprises 500 mg to 650 mg of amikacin or a pharmaceutically acceptable salt thereof encapsulated in a plurality of liposomes, wherein the lipid components of the plurality of liposomes consist of electrically neutral phospholipids and cholesterol. To provide an aerosolized pharmaceutical composition comprising a mixture of free amikacin or a pharmaceutically acceptable salt thereof and liposome-conjugated amikacin or a pharmaceutically acceptable salt thereof, the pharmaceutical composition is aerosolized via a nebulizer and administered to the patient's lungs once daily in a single dosing session for a period of at least 84 days. A pharmaceutical composition comprising the macrolide antibiotic, rifamycin compound, and ethambutol, which are orally administered to the patient during the administration period, wherein the patient achieves a negative MAC sputum culture on or before the 84th day after the start of treatment during the administration period.

2. The pharmaceutical composition according to claim 1, wherein the administration period is at least six months.

3. The pharmaceutical composition according to claim 1 or 2, wherein the macrolide antibiotic is azithromycin, clarithromycin, erythromycin, carbomycin A, josamycin, kitamycin, midecamycin, oleandmycin, solithromycin, spiramycin, troleandmycin, tylosin, roxithromycin, or a combination thereof.

4. The pharmaceutical composition according to claim 3, wherein the macrolide antibiotic is clarithromycin.

5. The pharmaceutical composition according to claim 3, wherein the macrolide antibiotic is azithromycin.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the rifamycin compound is rifampin.

7. The pharmaceutical composition according to any one of claims 1 to 5, wherein the rifamycin compound is rifabutin.

8. The pharmaceutical composition according to any one of claims 1 to 7, comprising 550 mg to 625 mg of amikacin or a pharmaceutically acceptable salt thereof encapsulated in the plurality of liposomes.

9. The pharmaceutical composition according to any one of claims 1 to 7, comprising 550 mg to 600 mg of amikacin or a pharmaceutically acceptable salt thereof encapsulated in the plurality of liposomes.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the amikacin or a pharmaceutically acceptable salt thereof is amikacin sulfate.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the plurality of liposomes include single-membrane vesicles, multi-membrane vesicles, or a combination thereof.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the electrically neutral phospholipid is electrically neutral phosphatidylcholine.

13. The pharmaceutical composition according to claim 12, wherein the electrically neutral phosphatidylcholine is dipalmitoylphosphatidylcholine (DPPC).

14. The pharmaceutical composition according to claim 13, comprising amikacin sulfate 70 mg / mL; DPPC 30-35 mg / mL; and cholesterol 15-17 mg / mL.

15. The pharmaceutical composition according to claim 14, further comprising 1.5% NaCl.

16. The pharmaceutical composition is the pharmaceutical composition according to claim 14 or 15, having a pH of 6.

5.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the aerosolized pharmaceutical composition is administered in less than 15 minutes during the single drug administration session.

18. The pharmaceutical composition according to any one of claims 1 to 17, wherein in the single drug administration session, the aerosolized pharmaceutical composition is administered over a period of 10 to 14 minutes.

19. The pharmaceutical composition according to any one of claims 1 to 18, wherein the patient achieves MAC sputum culture conversion, and MAC sputum culture conversion is defined as three consecutive negative MAC sputum cultures.

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