Method for treating non-tuberculous mycobacterial pulmonary infection

Abstract

Provided herein are methods for treating a pulmonary infection, eg, a nontuberculous mycobacterial pulmonary infection, in a patient in need thereof for at least one treatment cycle. The method includes administering to a patient's lungs a pharmaceutical composition containing a liposome-complexed aminoglycoside, the liposome-complexed aminoglycoside comprising an electrically neutral lipid and a lipid component comprising an aminoglycoside. The administration includes aerosolizing the pharmaceutical composition to provide an aerosolized pharmaceutical composition containing a mixture of free aminoglycoside and liposome-complexed aminoglycoside, and administering the aerosolized pharmaceutical composition to the patient's lungs via a nebulizer. The methods provided herein result in a change from baseline in a semiquantitative measure of mycobacterial cultures and / or a negative conversion of NTM cultures for the treated patient during or after the administration period.

Description

Technical Field

[0001]

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

Background Art

[0002]

[0002] Certain techniques suitable for administration by inhalation use liposomes, and lipid complexes provide an extended therapeutic effect of drugs 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 necessarily have 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. Because the infection rate is increasing, nontuberculous mycobacterial pulmonary disease (PNTM) is emerging as a public health concern in the United States. NTM are 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. ATS / IDSA PNTM reported that the two-year prevalence of NTM pulmonary infection was 8.6 / 100,000. The prevalence of NTM pulmonary infection increases with age and is 20.4 / 100,000 in at least those 50 years old and is particularly prevalent in women (median age: 66 years; women: 59%).

[0006]

[0006] In susceptible individuals, NTM pulmonary infection can be severe or life-threatening. Available treatments may have low tolerability and may have significant adverse events. The present invention addresses this and other needs by providing a method for treating NTM pulmonary infection in patients in need thereof.

Summary of the Invention

Means for Solving the Problems

[0007]

[0007] In one aspect, the present invention provides a method for treating or preventing non-tuberculous mycobacterial (NTM) infections (pulmonary infections caused by or due to one or more non-tuberculous mycobacteria) via administration of an effective amount of an inhaled composition comprising a liposome-complexed 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, bronchiectasis, asthma, or chronic obstructive pulmonary disease (COPD).

[0008]

[0008] In one embodiment, the NTM infection is an NTM lung infection selected from 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 complex, M. haemophilum, M. genavense, M. gordonae, M. ulcerans, M. fortuitum, M. fortuitum complex (M. fortuitum and M. chelonae) infections or combinations thereof. In a further embodiment, the NTM infection is an M. avium complex (MAC) (M. avium and M. intracellulare) infection. In one embodiment, the NTM infection is a refractory NTM lung 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 comprising electrically neutral lipids. In a further embodiment, the electrically neutral lipids comprise phosphatidylcholine and sterol (e.g., dipalmitoylphosphatidylcholine and cholesterol). In a further embodiment, the aminoglycoside is amikacin or a pharmaceutically acceptable salt thereof. In yet a further embodiment, the aminoglycoside is amikacin sulfate.

[0010]

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

[0011]

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

[0012]

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

[0013]

Table 1

[0014]

[0013] In one embodiment, the pharmaceutical composition provided herein is a dispersion of liposomes (i.e., a liposome dispersion or an aqueous liposome dispersion, which can 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 lipid to aminoglycoside in the aminoglycoside pharmaceutical composition (aminoglycoside liposome solution or suspension) is about 2:1, about 2:1 or less, about 1:1, about 1:1 or less, about 0.75:1 or less, or about 0.7:1. In another embodiment, the weight ratio of lipid to aminoglycoside in the composition is about 0.10:1 to about 1.25:1, about 0.10:1 to about 1.0:1, about 0.25:1 to about 1.25:1, about 0.5:1 to about 1:1.

[0016]

[0015] In one embodiment, the method provided herein includes administration of the liposome aminoglycoside composition via nebulization or aerosolization. Thus, the method in this embodiment involves the generation of an aerosolized aminoglycoside composition. In one embodiment, upon nebulization, the aerosolized composition has an aerosol droplet size of about 1 μm to about 3.8 μm, about 1.0 μm to 4.8 μm, about 3.8 μm to about 4.8 μm or about 4.0 μm to about 4.5 μm. In a further embodiment, the aminoglycoside is amikacin. In yet a further embodiment, the amikacin is amikacin sulfate.

[0017]

[0016] In one embodiment, about 70% to about 100% of the aminoglycoside present in the composition is complexed with liposomes, for example, encapsulated in a plurality of liposomes, prior to administration to a patient in need of treatment. In a further embodiment, the aminoglycoside is selected from the aminoglycosides provided in Table 1. In a further embodiment, the aminoglycoside is amikacin (e.g., as amikacin sulfate). In yet a further embodiment, about 80% to about 100% of the amikacin is complexed with liposomes or about 80% to about 100% of the amikacin is encapsulated in a plurality of liposomes prior to administration to a patient in need of treatment. In another embodiment, about 80% to about 100%, about 80% to about 99%, about 90% to about 100%, 90% to about 99% or about 95% to about 99% of the aminoglycoside present in the composition is complexed with liposomes prior to administration to a patient in need of treatment (i.e., prior to nebulization).

[0018]

[0017] In one embodiment, the percentage of the aminoglycoside complexed with (also referred to herein as "liposome-associated") liposomes after nebulization is about 50% to about 80%, about 50% to about 75%, about 50% to about 70%, about 55% to about 75% or about 60% to about 70%. In a further embodiment, the aminoglycoside is selected from the aminoglycosides provided in Table 1. In a further embodiment, the aminoglycoside is amikacin. In yet a further embodiment, the amikacin is amikacin sulfate. In one embodiment, the aerosolized (i.e., after nebulization) composition comprises about 65% to about 75% liposome-complexed aminoglycoside and about 25% to about 35% free aminoglycoside. In a further embodiment, the aminoglycoside is amikacin. In yet a further embodiment, the amikacin is amikacin sulfate.

[0019]

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

[0020]

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

[0021]

[0020] In one embodiment, the concentration of aminoglycoside in the liposomal 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 still a further embodiment, the aminoglycoside is amikacin (for example, amikacin sulfate).

Brief Description of the Drawings

[0022]

Figure 1

[0021] It is a diagram showing the test design of a randomized double-blind placebo-controlled trial of liposome-complexed amikacin in patients with refractory non-tuberculous mycobacterial (NTM) pulmonary infection as described in Example 1.

Figure 2

[0022] It is a diagram showing the patient distribution for a randomized double-blind placebo-controlled trial of liposome-complexed amikacin in patients with refractory non-tuberculous mycobacterial pulmonary 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] 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, it is a graph showing the mean change from the baseline of the complete semi-quantitative scale of acid-fast bacilli culture on a logarithmic scale (LS) as a function of the study day.

Figure 5

[0025] Figure 5 (upper figure) is a bar graph showing the percentage of patients with NTM culture negative conversion at various time points during the 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 negative conversion at various time points.

Figure 6

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

Figure 7

[0027] Figure 7 (upper figure) is a graph showing the change from the baseline in the 6-minute walk test on day 84 and day 168 (mITT population), and Figure 7 (lower figure) is a graph of the mean change from the baseline of the walking distance (meters) in the 6MWT of patients receiving LAI on 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 on day 84 and day 168 (all patients). Figure 8 (lower figure) is a graph showing the mean change from the baseline of the walking distance (meters) in the 6MWT from day 84 to day 168 for patients with culture negative conversion (three or more negative cultures) versus patients without culture negative conversion (last observation carried forward, modified intent to treat population).

Figure 9

[0029] Figure showing the study design of a randomized placebo - controlled trial of liposomal - encapsulated amikacin (ARIKAYCE or LAI) in patients with non - cystic fibrosis (non - CF) Mycobacterium avium complex (MAC) lung infection as described in Example 2.

Mode for Carrying Out the Invention

[0023]

[0030] In part, the invention described herein is directed to a method for treating lung infections in patients in need thereof, for example, administering an aminoglycoside pharmaceutical composition to the lungs of the patient, for example, via nebulization.

[0024]

[0031] As used herein, the term “about” refers to plus or minus 10 percent of the subject modified by “about”.

[0025]

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

[0026]

[0033] As used herein, “preventing” can mean completely preventing an infection or disease, or preventing the occurrence of symptoms of the infection or disease; delaying the onset of the infection or disease or its symptoms; or reducing the severity of an infection or disease or its symptoms that subsequently occur.

[0027]

[0034] The term "antibacterial" is approved in the art and refers to the ability of the compounds of the present 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 the art 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 an amount of an aminoglycoside (e.g., amikacin) used in the present invention that is sufficient to result in a desired therapeutic response. The effective amount of the compositions provided herein includes both free and liposome-complexed aminoglycosides. For example, in one embodiment, the liposome-complexed aminoglycoside includes an aminoglycoside encapsulated within or complexed with a liposome, or a combination thereof.

[0030]

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

[0031]

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

[0032]

[0039] "Nebulizer" or "aerosol generating device" is a device that converts a liquid into an aerosol of a size that can be inhaled into the airway. Pneumonic, ultrasonic, electronic nebulizers, e.g., passive electronic mesh nebulizers, active electronic mesh nebulizers and vibrating mesh nebulizers are suitable for use with the present invention when a particular nebulizer discharges an aerosol having the required properties at the required discharge rate.

[0033]

[0040] The process of converting bulk liquid into small droplets by air pressure is called atomization. The operation of a pneumatic nebulizer requires a supply of pressurized gas as the driving force for liquid atomization. An ultrasonic nebulizer uses the electrical power introduced by a piezoelectric element in a liquid reservoir to convert the liquid into respirable droplets. Various types of nebulizers are described in Respiratory Care, Volume 45, Number 6, pages 609 - 622 (2000), the entire disclosure of which is incorporated herein by reference. The terms "nebulizer" and "aerosol generator" are used interchangeably throughout the specification. The terms "inhalation device", "inhalation system" and "atomizer" are also used interchangeably in the literature with the terms "nebulizer" and "aerosol generator".

[0034]

[0041] The "mass median diameter" or "MMD" is determined by laser diffraction or impaction measurement and is the mean particle diameter on a mass basis.

[0035]

[0042] The "aerodynamic median diameter" or "MMAD" is normalized with respect to the aerodynamic separation of aqueous aerosol droplets and is determined by impaction measurement, for example, by an Andersen Cascade Impactor (ACI) or a Next Generation Impactor (NGI). In one embodiment, the gas flow rate 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] Non-tuberculous mycobacteria (NTM) are organisms found in soil and water that can cause severe lung disease in susceptible individuals, and currently there are limited effective treatments for this and no approved treatment. The prevalence of NTM disease has been reported to be increasing and is thought to be higher than the prevalence of tuberculosis in the United States according to a report by the American Thoracic Society. Epidemiological studies by the National Center for Biotechnology Information indicate that the presence of NTM infections is likely increasing in developing countries due to the introduction of tap water. Women with a characteristic phenotype are thought to be at high risk of acquiring NTM infections, along with patients with abnormalities in the cystic fibrosis transmembrane conductance regulator. Generally, the high-risk groups for increased morbidity and mortality with NTM lung disease are those with cavitary lesions, low body mass index (BMI), advanced age, and a high comorbidity index.

[0037]

[0044] NTM lung disease is often a chronic condition that can lead to progressive inflammation and lung damage, characterized by bronchiectasis and cavitary disease. NTM infections often require long-term hospitalization for medical management. Treatment usually involves multi-drug regimens that can be poorly tolerated and of limited effectiveness, 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 in the United States visited a physician during 2011.

[0038]

[0045] Management of lung disease caused by non-tuberculous mycobacteria (NTM) infections involves long-term multi-drug regimens, which are often associated with drug toxicity and sub-optimal outcomes. Achieving NTM culture negativity is one of the goals of treatment and represents the most clinically important microbiological endpoint in patients with NTM lung infections.

[0039]

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

[0040]

[0047] A treatment response can be any response that a user (e.g., a clinician) recognizes as an effective response to treatment. A treatment response generally is a reduction, inhibition, delay, or prevention of the growth or propagation of one or more NTMs, or the killing of one or more NTMs. A treatment response can also be reflected in an improvement in lung function, such as the forced expiratory volume in one second (FEV 1 ). In one embodiment in which a patient is being treated for NTM pulmonary infection, the treatment response is measured as a change from baseline in a complete semi-quantitative measure of acid-fast bacilli culture or an improvement in walking distance in a six-minute walk test (6MWT). Further, based on the evaluation of the treatment response, it is within the skill of the art to determine an appropriate treatment period, an appropriate dosage, and any possible combination therapies.

[0041]

[0048] The NTM pulmonary infections treatable by the methods and compositions described herein are, 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 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 combinations thereof. In a further embodiment, the non-tuberculous mycobacterial pulmonary infection is M. avium complex (MAC) (M. avium and M. intracellulare), M. abscessus or M. avium. In a further embodiment, the M. avium infection is M. avium subsp. hominissuis. In one embodiment, the non-tuberculous mycobacterial pulmonary infection is M. avium complex (MAC) (M. avium and M. intracellulare). In another embodiment, the NTM pulmonary infection is a refractory non-tuberculous mycobacterial pulmonary infection.

[0042]

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

[0043]

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

[0044]

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

[0045]

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

[0046]

Table 2

[0047]

[0053] In one embodiment, the pharmaceutical composition comprises a combination of an aminoglycoside or a pharmaceutically acceptable salt thereof, for example, a combination of two or more aminoglycosides or pharmaceutically acceptable salts thereof shown in Table 2. In one embodiment, a composition comprising a liposome-complexed aminoglycoside comprises from 1 to about 5 aminoglycosides or pharmaceutically acceptable salts thereof. In another embodiment, a composition comprising a liposome-complexed aminoglycoside comprises at least 1, at least 2, at least 3, at least 4, at least 5 or at least 6 (or pharmaceutically acceptable salts of said aminoglycosides) of the aminoglycosides shown in Table 2. In another embodiment, the pharmaceutical composition comprises from 1 to 4 aminoglycosides or pharmaceutically acceptable salts thereof. In a further embodiment, the combination comprises amikacin, for example, as amikacin sulfate.

[0048]

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

[0049]

[0055] In one aspect, the present invention provides a method for treating or providing prophylaxis against NTM lung infection. The treatment is achieved via delivery of a composition by inhalation via nebulization of a 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 of Tables 1 and / or 2, or a pharmaceutically acceptable salt thereof.

[0050]

[0056] The pharmaceutical composition provided herein is a liposomal dispersion comprising an aminoglycoside complexed to liposomes, for example, an aminoglycoside encapsulated in a plurality of liposomes. The pharmaceutical composition is a dispersion comprising a "liposome-complexed aminoglycoside" or an "aminoglycoside encapsulated in liposomes". "Liposome-complexed aminoglycoside" includes embodiments in which an aminoglycoside (or combination of aminoglycosides) is encapsulated in liposomes, and as part of a complex with liposomes, or as liposomes in which the aminoglycoside can be in the aqueous phase or the hydrophobic bilayer phase or the interfacial head region of the liposomal bilayer, and includes any form of aminoglycoside composition in which at least about 1% by weight of the aminoglycoside is associated with the liposomes.

[0051]

[0057] In one embodiment, the lipid component of the liposome or liposomes comprises an electrically neutral lipid, a positively charged lipid, a negatively charged lipid, or a combination thereof. In another embodiment, the lipid component comprises an electrically neutral lipid. In a further embodiment, the lipid component consists essentially of electrically neutral lipids. In still a further embodiment, the electrically neutral lipids include sterols and phospholipids. In still 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 the aminoglycoside or a pharmaceutically acceptable salt thereof is encapsulated within a plurality of liposomes. Further, liposome-complexed aminoglycosides represent any composition, solution or suspension in which at least about 1% by weight of the aminoglycoside is associated with lipid, either as part of a complex with the liposome or as any of the liposomes in which the aminoglycoside can be in the aqueous phase or the hydrophobic bilayer phase or the interfacial head region of the liposome bilayer. In one embodiment, prior to nebulization, at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% of the aminoglycoside in the composition is so associated. In one embodiment, the association is measured by separation through a filter in which the lipid and the drug associated with the lipid are retained (i.e., are in the retentate) and the free drug is in the filtrate.

[0053]

[0059] The methods provided herein include administering to a patient in need thereof a composition comprising an aminoglycoside or a pharmaceutically acceptable salt thereof encapsulated within a plurality of liposomes. One or more lipids can be used to form the plurality of liposomes. In one embodiment, the one or more lipids are synthetic, semi-synthetic or natural lipids including phospholipids, tocopherols, sterols, fatty acids, negatively charged lipids, cationic lipids or combinations thereof. In one embodiment, the lipid component of the plurality of liposomes 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 a plurality of 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); soya counterparts, soy phosphatidylcholine (SPC); SPG, SPS, SPI, SPE, and SPA; hydrogenated eggs and soya counterparts (e.g., HEPC, HSPC), phospholipids containing fatty acid chains of 12 to 26 carbon atoms at the 2 and 3 positions of glycerol and various head groups at the 1 position of glycerol formed by ester bonds, including choline, glycerol, inositol, serine, ethanolamine, and the corresponding phosphatidic acid. The carbon chains of these fatty acids can be saturated or unsaturated, and the phospholipids can be made from fatty acids of various chain lengths and various degrees of unsaturation.

[0055]

[0061] In one embodiment, the lipid component of the plurality of liposomes includes dipalmitoylphosphatidylcholine (DPPC), which is a major component of natural lung surfactant. In one embodiment, the lipid component of the plurality of liposomes includes DPPC and cholesterol, or consists essentially of DPPC and cholesterol, or consists of DPPC and cholesterol. In a further embodiment, DPPC and cholesterol have a molar ratio within 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 still a further embodiment, DPPC and cholesterol have a molar ratio of about 2:1 or about 1:1.

[0056]

[0062] Other examples of lipids for use with the methods and compositions described herein include mixed phospholipids and monoacylated phospholipids such as dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl phosphatidylcholine (DPPC), dipalmitoyl phosphatidylglycerol (DPPG), distearoyl phosphatidylcholine (DSPC), distearoyl phosphatidylglycerol (DSPG), dioleoyl phosphatidylethanolamine (DOPE), palmitoyl stearoyl phosphatidylcholine (PSPC), and for example, mono-oleoyl-phosphatidylethanolamine (MOPE), but are not limited thereto.

[0057]

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

[0058]

[0064] In one embodiment, at least one cationic lipid (lipid having a positive charge) is provided in the lipid component of the plurality of liposomes present in the liposomal aminoglycoside composition described herein for use in a method of treating NTM pulmonary infection in a patient in need thereof. 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 having a carbon chain length of 12 to 26 carbon atoms that are saturated or unsaturated. Some specific examples include myristylamine, palmitylamine, laurylamine, and stearylamine, dilauroyl ethylphosphocholine (DLEP), dimyristoyl ethylphosphocholine (DMEP), dipalmitoyl ethylphosphocholine (DPEP), and distearoyl ethylphosphocholine (DSEP), N-(2,3-di-(9-(Z)-octadecenyl oxy)-prop-1-yl-N,N,N-trimethylammonium chloride (DOTMA), 1,2-bis(oleoyloxy)-3-(trimethylammonio)propane (DOTAP), and combinations thereof, but are not limited thereto.

[0059]

[0065] In one embodiment, at least one anionic lipid (lipid having a negative charge) is provided in the lipid component of the plurality of liposomes present in the liposomal aminoglycoside composition described herein for use in a method of treating NTM pulmonary infection in a patient in need thereof. Lipids having a negative charge that can be used 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] Although not wishing to be bound by theory, phosphatidylcholines such as DPPC assist in the uptake of aminoglycoside agents by cells in the lung (e.g., alveolar macrophages) and help retain aminoglycosides in the lung. Lipids having a negative charge, such as PG, PA, PS, and PI, are thought to play a role in reducing particle aggregation and in the transport (transcytosis) of the composition across the lung for the persistence of the active characteristics of the inhalant composition as well as for systemic uptake. Although not wishing to be bound by theory, sterol compounds are thought to affect the release characteristics of the composition.

[0061]

[0067] A liposome is a completely closed lipid bilayer membrane that contains a trapped volume of water. Liposomes can be unilamellar vesicles (having a single membrane bilayer) or multilamellar vesicles (onion-like structures characterized by multiple membrane bilayers separated from each other by aqueous layers) or combinations thereof. The bilayer consists of two lipid monolayers having a hydrophobic "tail" region and a hydrophilic "head" region. The structure of the membrane bilayer is such that the hydrophobic (nonpolar) "tails" of the lipid monolayers face towards the center of the bilayer while the hydrophilic "heads" face towards the aqueous phase.

[0062]

[0068] The weight ratio of lipid to aminoglycoside in the pharmaceutical composition provided herein (the weight ratio is also referred to as "lipid:aminoglycoside" herein) is, in one embodiment, 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 composition provided herein is 0.7:1.0 or about 0.7:1.0 on a weight basis. In another embodiment, the L:D ratio in the liposome provided herein is 0.75:1 or less (on a weight basis). In one embodiment, the lipid:aminoglycoside weight ratio (lipid to aminoglycoside weight ratio) is from about 0.10:1.0 to about 1.25:1.0, from about 0.25:1.0 to about 1.25:1.0, from about 0.50:1.0 to about 1.25:1.0, or from about 0.6:1 to about 1.25:1.0. In another embodiment, the lipid to aminoglycoside weight ratio is from about 0.1:1.0 to about 1.0:1.0, or from about 0.25:1.0 to about 1.0:1.0, or from about 0.5:1 to 1:1.0.

[0063]

[0069] The lipid to aminoglycoside weight ratio in the composition provided herein in another embodiment 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 from about 0.5:1.0 to about 0.8:1.0.

[0064]

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

[0065]

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

[0066]

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

[0067]

[0073] In one embodiment, the liposomes are produced by sonication, injection, homogenization, swelling, electroformation, inverted emulsion or reverse-phase evaporation methods. The Bangham method (J. Mol. Biol. (1965)) produces normal multilamellar vesicles (MLV). Lenk et al. (U.S. Pat. Nos. 4,522,803, 5,030,453 and 5,169,637), Fountain et al. (U.S. Pat. No. 4,588,578) and Cullis et al. (U.S. Pat. No. 4,975,282) disclose methods for producing multilamellar liposomes having a substantially equal interphase solute distribution in each of their aqueous compartments. Paphadjopoulos et al., U.S. Pat. No. 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] Unilamellar vesicles can be produced from MLV by several techniques, such as the injection techniques of U.S. Pat. Nos. 5,008,050 and 5,059,421. Sonication and homogenization can be used to produce smaller unilamellar liposomes from larger liposomes (see, for example, Paphadjopoulos et al. (1968); Deamer and Uster (1983); and Chapman et al. (1968)).

[0069]

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

[0070]

[0076] To produce liposomes for use in the pharmaceutical compositions provided herein, techniques for producing large unilamellar vesicles (LUV), such as reverse phase evaporation, injection methods, and surfactant dilution, can be used. A review of these and other methods for producing 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, see also Szoka, Jr. et al. (Ann. Rev. Biophys. Bioeng. 9, 1980, p. 467), which is incorporated herein by reference in its entirety for all purposes.

[0071]

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

[0072]

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

[0073]

[0079] In one embodiment, the pharmaceutical composition comprises liposomes having an average diameter in the range of from about 0.01 micron to about 3.0 microns, such as from about 0.2 to about 1.0 micron, as measured by light scattering prior to atomization. In one embodiment, the average diameter of the liposomes in the composition is from about 200 nm to about 300 nm, from about 210 nm to about 290 nm, from about 220 nm to about 280 nm, from about 230 nm to about 280 nm, from about 240 nm to about 280 nm, from about 250 nm to about 280 nm, or from about 260 nm to about 280 nm. The sustained activity profile of the liposome product is adjustable by the nature of the lipid membrane and by including other excipients in the composition.

[0074]

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

[0075]

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

[0076]

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

[0077]

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

[0078]

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

[0079]

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

[0080]

[0086] In one embodiment, following the administration period, an off period of from about 15 to about 200 days follows, for example, from about 15 days to about 150 days or from about 15 days to about 75 days, from about 15 days to about 35 days, or from about 20 days to about 35 days, or from about 25 days to about 75 days, or from about 35 days to about 75 days or from about 45 days to about 75 days. In another embodiment, the off period is about 28 days or about 56 days. In other embodiments, the off period is about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 days, although in other embodiments the off period is about 56 days.

[0081]

[0087] In one embodiment, a patient in need thereof is administered a liposome-complexed aminoglycoside composition in a treatment cycle that includes a dosing 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 2 times, for example, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times. In another embodiment, the treatment cycle is repeated at least 3 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 methods provided herein do not include an off period and instead include only the dosing period. In a further embodiment, one of the dosing periods shown in Table 3 is used in the methods provided herein. In a further embodiment, the patient is administered the liposome aminoglycoside composition once daily during the dosing period of a single dosing session.

[0083]

Table 3-1

[0084]

Table 3-2

[0085]

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

[0086]

[0090] In one embodiment, the pharmaceutical composition provided herein comprises at least one aminoglycoside, at least one lipid 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 as the two ratios are fixed, for example, at about 0.7:1 on a weight basis), the viscosity of the solution also increases, which slows the spraying time.

[0089]

[0092] As provided throughout, the methods described herein include administering to a patient in need of treatment for NTM lung infection an effective amount of a liposomal aminoglycoside composition via inhalation. In one embodiment, the inhalation delivery is performed 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 pneumonic (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 infections is effected via administration during a once-daily dosing session of a liposome-complexed aminoglycoside composition via a nebulizer to a patient in need thereof. In a further embodiment, the aminoglycoside is amikacin, such as amikacin sulfate. In a further embodiment, the lipid component of the liposome comprises DPPC and cholesterol. In yet a further embodiment, the nebulizer is one of the nebulizers described in U.S. Patent Application Publication No. 2013 / 0330400, which is hereby incorporated by reference in its entirety for all purposes.

[0092]

[0095] The principles of operation of pneumatic nebulizers are generally known to those of skill in the art and are described, for example, in Respiratory Care, Vol. 45, No. 6, pp. 609-622 (2000). Briefly, the supply of pressurized gas is used as the driving force for the atomization of liquid in a pneumatic nebulizer. Compressed gas is delivered, which creates a region of negative pressure. The aerosolized solution is then delivered into the gas stream and sheared into a liquid film. This film is unstable and breaks due to surface tension to form droplets. Small particles, i.e., particles having the above MMAD and FPF characteristics, can then be formed by placing an obstruction wall in the aerosol stream. In one embodiment of a pneumatic nebulizer, the gas and solution are mixed before exiting the outlet port (nozzle) and interacting with the obstruction 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, O 2 and / or CO 2 is.

[0093]

[0096] In one embodiment, the size and ejection rate of the droplets can be adjusted in a pneumonic nebulizer. However, it should be considered whether the composition to be atomized and the properties of the composition (e.g., the percentage of associated aminoglycoside) are changed by the improvement of the nebulizer. For example, in one embodiment, the gas velocity and / or the velocity of the pharmaceutical composition are modified to achieve the ejection rate and droplet size of the present invention. In addition or alternatively, the flow rate of the gas and / or the solution can be adjusted to achieve the droplet size and ejection rate of the present invention. For example, in one embodiment, an increase in the gas velocity decreased the droplet size. In one embodiment, the ratio of the pharmaceutical composition flow to the gas flow is adjusted to achieve the droplet size and ejection rate of the present invention. In one embodiment, an increase in the ratio of the liquid to gas flow increases the particle size.

[0094]

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

[0095]

[0098] In one embodiment, a liquid storage bag is used to capture the aerosol during the atomization process, and then the aerosol is provided to the subject via inhalation. In another embodiment, the nebulizer provided herein includes an open port design with a valve. In this embodiment, when the patient inhales through the nebulizer, the ejection volume of the nebulizer increases. During the exhalation phase, the one-way valve diverts the patient flow so that it exits the nebulizer chamber.

[0096]

[0099] In one embodiment, the nebulizer provided herein is a continuous nebulizer. In other words, there is no need to refill the nebulizer with the pharmaceutical composition while administering the dosage. Rather, the nebulizer has a limit volume 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 thus does not generate an air flow. In one embodiment, the aerosol is generated by an aerosol head that enters the mixing chamber of the device. When the patient inhales, air enters the mixing chamber through a one-way inhalation valve behind the mixing chamber and carries the aerosol to the patient through the mouthpiece. During exhalation, the patient's breath flows through a one-way exhalation valve on the mouthpiece of the device. In one embodiment, the cycle in which the nebulizer continues to generate the aerosol into the mixing chamber and then this is drawn in by the subject during the next breath continues until the drug reservoir of the nebulizer is empty.

[0098]

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

[0099]

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

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

[0102]

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

[0103]

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

[0104]

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

[0105]

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

[0106]

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

[0107]

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

[0108]

[0111] In another embodiment, the methods provided herein are practiced for the treatment or prevention of one or more NTM lung infections in a patient 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 in need of treatment for NTM lung infection is a patient with bronchiectasis. In one embodiment, the bronchiectasis is non-cystic fibrosis (CF)-related bronchiectasis. In another embodiment, the bronchiectasis is CF-related in a patient in need of treatment.

[0110]

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

[0111]

[0114] In one embodiment, the patient in need of treatment by one of the methods described herein is a patient with cystic fibrosis, bronchiectasis, ciliary dyskinesia, chronic smoker, chronic obstructive pulmonary disease (COPD), or a patient who was previously non-responsive to treatment. In another embodiment, the patient with cystic fibrosis is treated for NTM lung infection by one of the methods provided herein. In yet another embodiment, the patient is a patient with bronchiectasis, COPD, or 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] The patient subjected to the methods described herein has, in one embodiment, a co-existing condition. For example, in one embodiment, the patient in need of treatment by one of the methods described herein has, in addition to NTM lung 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 abnormality, tracheal abnormality, bronchial abnormality, aspergillosis, HIV, or bronchiectasis.

[0113]

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

[0114]

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

[0115]

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

[0116]

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

[0117]

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

[0118]

[0121] In one embodiment, the liposomal aminoglycoside composition provided herein is administered to a patient in need of treatment for NTM lung disease, together with an additional therapy.

[0119]

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

[0120]

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

[0121]

[0124] In one embodiment, the one or more additional therapeutic agents 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 in need of treatment for NTM lung disease, together with one or more additional therapeutic agents, and the one or more additional therapeutic agents are rifamycin compounds. In a further embodiment, the rifamycin is rifampin. In another embodiment, the rifamycin is rifabutin, rifapentine, rifaximin, or a combination thereof.

[0123]

[0126] In a further embodiment, the one or more additional therapeutic agents 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 in need of NTM treatment, and the second therapeutic agent is a second aminoglycoside. In a further embodiment, the second aminoglycoside is amikacin, apramycin, albekacin, astromicin, bekanamycin, bohromycin, bulramycin, capreomycin, dibekacin, dactimicin, etimicin, flamicetin, gentamicin, H107, hygromycin, hygromycin B, inosamycin, K-4619, isepamicin, KA-5685, kanamycin, neomycin, netilmicin, paromomycin, plazomycin, ribostamycin, sisomicin, rhodostreptomycin, solbistin, spectinomycin, sporaricin, streptomycin, tobramycin, verdamycin, vertilmicin, pharmaceutically acceptable salts thereof, or combinations thereof. In a further embodiment, the second aminoglycoside is administered intravenously or via inhalation. In one embodiment, the second aminoglycoside is streptomycin.

[0125]

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

Examples

[0126]

[0129] The present invention is further illustrated by reference to the following examples. However, it should be noted that, like the above embodiments, these examples are illustrative and are in no way to be construed as limiting the scope of the present invention.

[0127] Example 1: Randomized double-blind trial of liposomal inhaled amikacin (LAI) in patients with non-tuberculous mycobacterial (NTM) lung disease (LD)

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

[0128]

[0131] The LAI composition had the following components.

[0129]

Table 5

[0130]

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

[0131]

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

[0132]

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

[0133]

[0135] Eighty and 59 patients complete the DB and OL phases, respectively, and the trial is completed. The demographics and baseline characteristics of the mITT population are provided in Table 5 below.

[0134]

Table 6

[0135]

[0136] The sample population enrolled in the mITT trial showed the following: (1) 17 of the patients had concurrent lung disease, with 17 having cystic fibrosis; (2) an average age of 59 years, including young cystic fibrosis patients; (3) lung abnormalities, including 68 patients with cavitary lesions and 21 patients with nodular disease further including small cavitary disease; (4) a mean BMI of 21.98, compared to corresponding CDC data collected between 2007 and 2010 showing that the average body mass index (BMI) in the United States was 28.6 for adult men and 28.7 for adult women; and (5) an average baseline of approximately 441 m for all patients, with both arms having approximately the same mean baseline 6-minute walk distance.

[0136]

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

[0137]

[0138] Figure 4 is a graph showing the mean change from baseline in the complete semi - quantitative scale of mycobacterial culture (mITT population) as a function of the study 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 a one - step reduction in the treatment arm vs the placebo arm during the double - blind phase.

[0138]

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

[0139]

[0140] On the 168th day, in the prior LAI arm versus the prior placebo arm, significantly more MAC-infected patients had a sputum culture that was NTM-negative (P = .026) (Table 6). In the analysis of the subgroup of patients with NTM pulmonary infections refractory to guideline-based therapies (Tables 7 and 8), LAI appeared superior to placebo with respect to NTM-negative sputum cultures in patients with non-CF underlying the lung disease and MAC infection. The subgroup of patients with non-CF MAC infection showed positive efficacy results within the time frame of the trial (i.e., 12-week double-blind phase and 12-week open-label phase).

[0140]

[0141] The time to culture conversion showed that the proportion of patients in the LAI arm who became culture-negative at all visits during the double-blind phase (days 28, 56, and 84) was significantly higher statistically (Figure 5, upper figure). Specifically, for 11 out of 44 patients in the LAI group versus 3 out of 45 patients in the placebo group, LAI achieved statistical significance in the achievement of negative cultures at day 84 (P = .01) (Figure 5, upper figure). Compared to placebo, LAI achieved statistical significance with respect to the proportion of patients with MAC infection who achieved culture negativity at day 56 (LAI, 10 patients / 29 vs. placebo, 2 patients / 28; P = .0144) and at day 84 (LAI, 10 patients / 29 vs. placebo, 3 patients / 28; P = .0273) (Figure 5, lower figure).

[0141]

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

[0142]

Table 7

[0143]

Table 8

[0144]

Table 9

[0145]

[0143] The 6-minute walk test (6MWT) evaluated the impact of LAI on overall physical function or ability. The results of the 6MWT endpoints (change from baseline from day 1 to the last 84 days of the double-blind trial) are provided in Figures 7 and 8. LAI demonstrated statistical significance in the 6MWT in the double-blind phase (LAI vs placebo: 23.895 vs -25.032 meters, P = 0.009). The mean change from baseline to day 84 in walking distance (meters) in the 6MWT was significantly higher in patients receiving LAI compared to placebo (20.64 m vs -25.03 m) (Figure 7, lower figure). In the open-label phase, patients in the LAI arm continued to improve in the 6MWT, and patients in the placebo group who initiated LAI showed a dramatic 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, a significant difference in the mean change in 6MWT score from baseline to day 168 was seen compared to patients who did not have a persistent culture-negative state (55.75 m vs -13.42 m) (Figure 8, lower figure).

[0146]

[0144] Patients with treatment-refractory NTM pulmonary infections showed improvement in walking distance in the 6MWT when LAI was added to the background of their guideline-based treatment. During the trial, patients who remained culture-negative achieved better physical functional ability as evaluated by the 6MWT.

[0147]

[0145] The sample population enrolled in the mITT trial showed the following regarding culture conversion 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 conversion; (2) 15 patients had MAC and 1 patient had M. abscessus; (3) Despite non-LAI treatment methods lasting over 24 months, 8 patients did not show treatment success, despite non-LAI treatment methods lasting 12 - 24 months, 4 patients did not show treatment success, and despite non-LAI treatment methods lasting 6 - 12 months, 4 patients did not show treatment success; (4) 7 patients showed nodular disease, 2 patients showed nodular disease and small cavitary lesions, and 7 patients showed cavitary lesions; (5) 11 patients started conversion on or before day 56 after the start of the LAI treatment method, 2 patients converted on day 84 after the start of the LAI treatment method, and 3 patients converted on day 112 after the start of the LAI treatment method; and (6) The 6MWT for converters (n = 16) vs non-converters (n = 43) on day 168 had a p-value of 0.0034 and was 89.34 meters (converters) vs 3.85 meters (non-converters).

[0148]

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

[0149]

[0147] Further, patients transitioning from the LAI to the open-label phase in the double-blind phase (see Figure 1 for the study design) were found to continue to improve. Further, patients transitioning from placebo to the open-label phase show a dramatic decrease in their rate of decline. Adverse events (TEAEs) that developed under treatment were mostly of mild or moderate severity, and the majority of TEAEs were, in fact, respiratory-related (Table 9). Local events and exacerbations of underlying pulmonary disease infections were the most common TEAEs. A small number of patients discontinued the investigational drug due to these events.

[0150]

Table 10

[0151] Example 2: Trial of Liposomal Amikacin Inhalation (LAI) in Patients with Non-CF M. avium complex (MAC) Lung Infection

[0148] LAI (also referred to herein as "Arikayce™" or "ARIKAYCE™") is a sustained-release lipid composition of amikacin under development for the treatment of patients with refractory NTM lung disease. In this trial, the efficacy, safety, and tolerability of LAI are evaluated in non-cystic fibrosis patients with M. avium complex (MAC) lung infection. Figure 9 is a flowchart showing the trial design.

[0152]

[0149] The LAI composition contains the following components:

[0153]

Table 11

[0154]

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

[0155]

Table 12

[0156]

[0151] Patients are randomized 2:1 into two groups: (i) LAI 590 mg + background therapy and (ii) background therapy only. Each patient group is subjected to daily dosing for 8 months. Primary culture conversion is evaluated at 6 months. The 6MWT is also performed at 6 months for each patient.

[0157]

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

[0158]

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

[0159] [

[0154] ] The embodiments illustrated and discussed in this specification are intended only to teach those skilled in the art the best mode known to the inventors for making and using the invention. As will be recognized by those skilled in the art in light of the above teachings, modifications and variations of the above-described embodiments of the invention are possible without departing from the invention. Accordingly, it is understood that the invention can be practiced otherwise than as specifically described within the scope of the claims and their equivalents. Accordingly, the foregoing description and drawings are merely illustrative, and the disclosure is more particularly set forth in the following claims.

Claims

1. A pharmaceutical composition for treating Mycobacterium avium complex (MAC) pulmonary infection in a patient in need of treatment, which is used in combination with a macrolide antibiotic, a rifamycin compound, and ethambutol, wherein the pharmaceutical composition contains 500 mg to 650 mg of amikacin or a pharmaceutically acceptable salt thereof encapsulated in a plurality of liposomes, and the lipid component of the plurality of liposomes consists of an electrically neutral phospholipid and cholesterol, The pharmaceutical composition is aerosolized via a nebulizer to provide an aerosolized pharmaceutical composition containing a mixture of free amikacin or a pharmaceutically acceptable salt thereof and liposome-complexed amikacin or a pharmaceutically acceptable salt thereof, and is administered to the patient's lungs once a day in a single dosing session for at least 84 days of dosing period. The macrolide antibiotic, rifamycin compound, and ethambutol are orally administered to the patient during the dosing period, and the patient achieves a negative MAC sputum culture on or before the 84th day after the start of treatment during the dosing period. A pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the dosing period is at least 6 months.

3. The macrolide antibiotic according to claim 1 or 2 is azithromycin, clarithromycin, erythromycin, carbomycin A, josamycin, kitasamycin, midecamycin, oleandomycin, solithromycin, spiramycin, troleandomycin, tylosin, roxithromycin, or a combination thereof. Pharmaceutical composition.

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, wherein the pharmaceutical composition contains 550 mg to 625 mg of amikacin or a pharmaceutically acceptable salt thereof encapsulated in a 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 a 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 comprises unilamellar vesicles, multilamellar 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 70 mg / mL of amikacin sulfate; 30 to 35 mg / mL of DPPC; and 15 to 17 mg / mL of cholesterol.

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

16. 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 in a single dosing session, the aerosolized pharmaceutical composition is administered in less than 15 minutes.

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

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

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