system for treatment or prophylaxis against pulmonary infection and use of a pharmaceutical formulat

专利摘要:
SYSTEM FOR TREATMENT OR PROPHYLAXIS AGAINST PULMONARY INFECTION AND USE OF A PHARMACEUTICAL FORMULATION THAT UNDERSTANDS LIPOSOMA-COMPLEX AMINOGLYcoside This document provides systems for the treatment of an individual with a lung infection, for example, non-tuberculous pulmonary mycobacterial lung infection, a pulmonary infection by Burkhardk , pulmonary infection associated with bonquiectasis or a pulmonary infection with Pseudomonas. The system includes a pharmaceutical formulation comprising a dispersion of liposomal aminoglycoside and the lipid component of the liposomes consisting essentially of electrically neutral lipids. The system also includes a nebulizer that generates an aerosol of the pharmaceutical formulation at a rate greater than about 0.53 g / min. the aerosol is released to an individual through inhalation for the treatment of lung infection.
公开号:BR112014029010B1
申请号:R112014029010-5
申请日:2013-05-21
公开日:2020-11-17
发明作者:Walter Perkins；Vladimir Malinin；Xingong Li；Brian Miller；Dominique Seidel；Philipp Holzmann；Harald Schulz；Michael Hahn
申请人:Insmed Incorporated；
IPC主号:

专利说明:

CROSS REFERENCE TO RELATED REQUESTS
[0001] This application claims priority benefit from US Provisional Application Number 61 / 649,830, filed on May 21, 2012, incorporated into this document as a reference in its entirety. BACKGROUND OF THE INVENTION
[0002] Certain technologies suitable for administration by inhalation use liposome and lipid complexes in order to provide a prolonged therapeutic effect of the drug in the lung. These technologies also provide a drug with sustained activity, and the ability to segment and increase the absorption of the drug in the disease sites.
[0003] The release of liposome inhalation is complicated due to its sensitivity to stress during nebulization, which can lead to changes in physical characteristics (eg, trapping, size). However, as long as changes in characteristics are reproducible and meet the acceptability criteria, they need not be prohibitive for pharmaceutical development.
[0004] Patients with cystic fibrosis (CF) have thick mucus and / or sputum secretions in the lungs, frequent consequent infections and biofilms resulting from bacterial colonizations. All of these fluids and materials create barriers to effective targeting of infections with aminoglycosides. Aminoglycoside liposomal formulations may be useful in combating bacterial biopellicles. SUMMARY OF THE INVENTION
[0005] The present invention provides methods for the treatment of various pulmonary infections, mycobacterial infections, including (for example, lung infections caused by non-tuberculous mycobacteria, also referred to herein as non-tuberculous mycobacterial infections (MNT)), by providing of systems for delivering liposomal aerosol formulations through inhalation. For example, the systems and methods provided herein can be used to treat an infection with pulmonary non-tuberculous mycobacteria such as, 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 or complex infection with M. fortuitum (M. fortuitum and chelonae).
[0006] In one aspect, the present invention provides a system for the treatment or provides prophylaxis against a lung infection. In one embodiment, the system comprises a pharmaceutical formulation comprising an aminoglycoside complexed to the liposome, wherein the formulation is a dispersion (for example, a liposomal solution or suspension), the lipid component of the liposome is composed of electrically neutral lipids, and a nebulizer which generates an aerosol of the pharmaceutical formulation at a rate greater than about 0.53 g / min. In one embodiment, the mass mean aerodynamic diameter (MMAD) of the aerosol is less than about 4.2 pm, as measured by the Andersen Cascade Impactor (ACI), about 3.2 pm to about 4.2 pm, as as measured by ACI, or less than about 4.9 pm, as measured by the Next Generation Impactor (NGI), or about 4.4 pm to about 4.9 pm, as measured by NGI.
[0007] In another embodiment, the system for the treatment or provision of prophylaxis against pulmonary infection comprises a pharmaceutical formulation comprising an aminoglycoside complexed to the liposome, wherein the formulation is a dispersion (for example, a liposomal solution or suspension), the lipid component of the liposome consists of electrically neutral lipids, and a nebulizer that generates an aerosol of the pharmaceutical formulation at a rate greater than about 0.53 g / min. The fine particle fraction (FPF) of the aerosol is greater than or equal to about 64%, as measured by the Andersen Cascade Impactor (ACI), or greater than or equal to about 51%, as measured by the Next Generation Impactor ( NGI).
[0008] In one embodiment, the system provided in this document comprises a pharmaceutical formulation consisting of an aminoglycoside. In another embodiment, the aminoglycoside is amikacin, apramycin, arbecacin, astromycin, capreomycin, dibecacin, framicetin, gentamicin, hygromycin B, isepamycin, kanamycin, neomycin, netylmycin, paromomycin, rodestreptomycin, ribostamycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, a combination of them. In yet another modality, the aminoglycoside is amikacin. In another embodiment, the aminoglycoside is selected from an aminoglycoside shown in Table A, below, or a combination thereof.

[0009] The pharmaceutical formulations provided herein are dispersions of liposomes (i.e., liposomal dispersions or aqueous dispersions of liposomes which can be either liposomal solutions or suspensions of liposomes). In one embodiment, the lipid component of the liposomes consists essentially of one or more electrically neutral lipids. In another embodiment, the electrically neutral lipid comprises a phospholipid and a sterol. In another embodiment, the phospholipid is dipalmitoylphosphatidylcholine (DPPC) and sterol is cholesterol.
[00010] In one embodiment, the lipid-to-drug ratio in the pharmaceutical aminoglycoside formulation (liposomal aminoglycoside solution or suspension) is about 2: 1, about 2: 1 or less, about 1: 1, about 1: 1 or less, or about 0.7: 1.
[00011] In one embodiment, the aerosolized aminoglycoside formulation, by nebulization, has an aerosol droplet size of about 1 pm to about 3.8 pm, about 1.0 pm to 4.8 pm , about 3.8 pm to about 4.8 pm, or about 4.0 pm to about 4.5 pm. In another modality, the aminoglycoside is amikacin. In yet another embodiment, amikacin is amikacin sulfate.
[00012] In one embodiment, about 70% to about 100% of the aminoglycoside present in the formulation is liposomally complexed, for example, encapsulated in a plurality of liposomes, prior to nebulization. In another embodiment, the aminoglycoside is selected from an aminoglycoside provided in Table A. In another embodiment, the aminoglycoside is an amikacin. In yet another embodiment, about 80% to about 100% of amikacin are liposomal complexed, or about 80% to about 100% of amikacin are encapsulated in a plurality of liposomes. In another embodiment, before nebulization, about 80% to about 100%, about 80% to about 99%, about 90% to about 100%, 90% and about 99%, or about 95 % to about 99% of the aminoglycoside present in the formulation are liposomally complexed before nebulization.
[00013] In one embodiment, the percentage of post-nebulization of aminoglycoside complexed to the liposome (also referred to herein as "associated liposomal" is about 50% to about 80%, from about 50% to about 75 %, from about 50% to about 70%, from about 55% to about 75%, or from about 60% to about 70% In another embodiment, the aminoglycoside is selected from an aminoglycoside provided in Table A. In an additional embodiment, the aminoglycoside is amikacin, and in yet another modality, amikacin is amikacin sulfate.
[00014] In another aspect, the present invention provides methods for the treatment or provision of prophylaxis against a lung infection. In one embodiment, lung infection is a lung infection caused by a Gram-negative bacterium (also referred to herein as a Gram-negative bacterial infection). In one embodiment, the lung infection is a Pseudomonas infection, for example, a Pseudomonas aeruginosa infection. In another embodiment, the lung infection is caused by one of the Pseudomonas species provided in Table B, below. In one embodiment, the patient is treated for mycobacterial lung infection with one of the systems provided in this document. In another embodiment, mycobacterial pulmonary infection is a pulmonary infection by non-tuberculous mycobacteria, a pulmonary infection by Mycobacterium abscessus or a pulmonary infection by Mycobacterium avium complex. In one or more of the previous modalities, the patient is a patient with cystic fibrosis.
[00015] In one embodiment, a patient with cystic fibrosis is treated for a pulmonary infection with one of the systems provided in this document. In another embodiment, lung infection is caused by Mycobacterium abscessus, Mycobacterium avium complex, or P. aeruginosa. In another embodiment, lung infection is caused by a non-tuberculous mycobacterium 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. intracellular e), 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. lenttflavum, M. celatum, M. fortuitum, M. fortuitum complex (M. fortuitum and chelonae) or a combination thereof.
[00016] In another aspect, a method is provided for the treatment or provision of prophylaxis against a lung infection in a patient. In one embodiment, the method comprises aerosolizing a pharmaceutical formulation comprising an aminoglycoside complexed to the liposome, wherein the pharmaceutical formulation is an aqueous dispersion of liposomes (for example, a liposomal solution or liposomal suspension), and is transformed into an aerosol at a rate greater than about 0.53 g / min. The method further comprises administering the pharmaceutical aerosol formulation to the patient's lungs; wherein the aerosol pharmaceutical formulation comprises a mixture of free aminoglycoside and aminoglycoside complexed with the liposome, and the lipid component of the liposome is composed of electrically neutral lipids. In another embodiment, the mass mean aerodynamic diameter (MMAD) of the aerosol is about 1.0 pm to about 4.2 pm as measured by ACI. In any of the process modalities, MMAD of the aerosol is from about 3.2 pm to about 4.2 pm as measured by ACI. In any of the preceding embodiments, the MMAD of the aerosol is about 1.0 pm to about 4.9 pm as measured by NGI. In any of the process modalities, the MMAD of the aerosol is from about 4.4 pm to about 4.9 pm as measured by NGI.
[00017] In one embodiment, the method comprises aerosolizing a pharmaceutical formulation comprising an aminoglycoside complexed to the liposome, wherein the pharmaceutical formulation is an aqueous dispersion and is aerosolized at a rate greater than about 0.53 g / min The method further comprises administering the pharmaceutical aerosol formulation to the patient's lungs; wherein the aerosol pharmaceutical formulation comprises a mixture of free aminoglycoside and aminoglycoside complexed to the liposome (e.g., liposome-encapsulated aminoglycoside), and the component of the liposome formulation is composed of electrically neutral lipids. In yet another embodiment, the fine particle fraction (FPF) of the aerosol is greater than or equal to about 64%, as measured by ACI, or greater than or equal to about 51%, as measured by NGI.
[00018] In another aspect, an aminoglycoside aerosol complexed to the liposome (for example, an aminoglycoside complexed to the liposome) is provided. In one embodiment, the aerosol comprises an aminoglycoside and a plurality of liposomes comprising DPPC and cholesterol, where about 65% to about 75% of the aminoglycoside is complexed with the liposome and the aerosol is generated at a rate greater than about 0, 53 g / min. In another embodiment, about 65% to about 75% of the aminoglycoside is made up of complexed liposomal, and the aerosol is generated at a rate greater than about 0.53 g / min. In either process, the aerosol is generated at a rate greater than about 0.54 g / min. In either process, the aerosol is generated at a rate greater than about 0.55 g / min. In any of the above embodiments, the aminoglycoside is selected from an aminoglycoside provided in Table A.
[00019] In one embodiment, the MMAD of the liposome-complexed aminoglycoside aerosol is about 3.2 pm to about 4.2 pm, as measured by ACI, or about 4.4 pm to about 4, 9 pm, as measured by NGI. In another embodiment, the aerosol comprises an aminoglycoside and a plurality of liposomes comprising DPPC and cholesterol, in which about 65% to about 75% of the aminoglycoside is complexed with the liposome (for example, encapsulated in which the plurality of liposomes), and the aerosolized liposomal aminoglycoside is generated at a rate greater than about 0.53 g / min. In another embodiment, the aminoglycoside is selected from an aminoglycoside provided in Table A.
[00020] In one embodiment, FPF of the complexed lipid aminoglycoside aerosol is greater than or equal to about 64%, as measured by the Andersen Cascade Impactor (ACI), or greater than or equal to about 51%, as measured by the Next Generation Impactor (NGI). In another embodiment, the aerosol comprises an aminoglycoside and a plurality of liposomes comprising DPPC and cholesterol, in which about 65% to about 75% of the aminoglycoside is complexed with the liposome, for example, encapsulated in the plurality of liposomes and the liposomal aminoglycoside in aerosol is generated at a rate greater than about 0.53 g / min. In either process, aerosol is generated at a rate greater than about 0.54 g / min. In either process, the aerosol is generated at a rate greater than or about 0.55 g / min. In any of the previous embodiments, the aminoglycoside is selected from an aminoglycoside provided in Table A.
[00021] In one embodiment, the aerosol comprises an aminoglycoside and a plurality of liposomes comprising DPPC and cholesterol, wherein about 65% to about 75% of the aminoglycoside is complexed with the liposome. In another embodiment, about 65% to about 75% of the aminoglycoside is encapsulated in the plurality of liposomes. In another embodiment, the aerosol is generated at a rate greater than about 0.53 g / min., Greater than about 0.54 g / min., Or greater than about 0.55 g / min. In another embodiment, the aminoglycoside is amikacin (for example, amikacin sulfate).
[00022] In one embodiment, the concentration of aminoglycoside in the aminoglycoside complexed to the liposome is about 50 mg / ml or higher. In another embodiment, the concentration of aminoglycoside in the aminoglycoside complexed to the liposome is about 60 mg / mL or higher. In another embodiment, the concentration of aminoglycoside in the aminoglycoside complexed to the liposome is about 70 mg / ml or more, for example about 70 mg / ml to about 75 mg / ml. In another embodiment, the aminoglycoside is selected from an aminoglycoside provided in Table A. In yet another embodiment, the aminoglycoside is amikacin (for example, amikacin sulfate). BRIEF DESCRIPTION OF THE DRAWINGS
[00023] Figure 1 shows a diagram of a nebulizer (aerosol generator) in which the present invention can be implemented.
[00024] Figure 2 is an enlarged representation of the nebulizer diagram shown in Figure 1.
[00025] Figure 3 shows a cross-sectional view of a generally known aerosol generator, as described in WO 2001/032246.
[00026] Figure 4 is an image of a PARI eFlow® nebulizer, modified for use with the aminoglycoside formulations described in this document, and an exploded membrane diagram of the nebulizer.
[00027] Figure 5 is a cross-sectional computed tomography (CT) image showing a membrane showing a relatively long nozzle portion.
[00028] Figure 6 is a cross-sectional computed tomography (CT) image of a stainless steel membrane showing a relatively short nozzle portion.
[00029] Figure 7 is an animated cross-sectional representation of the sputum / biofilm seen, for example, in patients with cystic fibrosis.
[00030] Figure 8 is a graph of the aerosol generation time when the liquid is completely released into the liquid reservoir (nebulization time) as a function of the initial gas cushion inside the liquid reservoir (VA).
[00031] Figure 9 is a graph of the negative pressure in the nebulizer as a function of the aerosol generation time until the complete release of the pharmaceutical formulation from the liquid reservoir (nebulization time).
[00032] Figure 10 is a graph of aerosol generation efficiency as a function of negative pressure in the nebulizer.
[00033] Figure 11 is a graph of the time period for aerosol generation when the liquid is completely released (time fogging) as a function of the ratio between the increase in the VRN volume of the liquid reservoir and the initial volume of the liquid in the inside the liquid reservoir (VL) (VRN / VL).
[00034] Figure 12 is a graph showing the MMAD of aerosol formulations as a function of the nebulization rate of the respective formulation.
[00035] Figure 13 is a graph showing the FPF of aerosol formulations as a function of the nebulization rate of the respective formulation.
[00036] Figure 14 is a schematic diagram of the system used for aerosol recovery for post-nebulization studies. DETAILED DESCRIPTION OF THE INVENTION
[00037] The invention described in this document is directed, in part, to systems for administering a pharmaceutical aminoglycoside formulation to an individual's lungs, for example, to treat a lung disorder.
[00038] The term "treatment" includes: (1) preventing or delaying the appearance of clinical symptoms of the disease, disorder or condition that develop in the individual who may be affected or predisposed to the disease, disorder or condition, but who has not yet experienced it or had clinical or subclinical symptoms of the disease, disorder or condition; (2) inhibition of the disease, disorder or condition (that is, preventing, reducing or delaying the development of the disease, or a relapse in the case of maintenance treatment, of at least one clinical or subclinical symptom of the same); and / or (3) relieving the condition (that is, causing the condition, disorder or condition to regress, or at least one of its clinical, or subclinical symptoms). The benefit to a treaty individual is either statistically significant or at least noticeable to the individual or the doctor.
[00039] In one embodiment, lung infections caused by bacteria are treatable with the systems and formulations provided in this document: Pseudomonas (for example, P. aeruginosa, P. paucimobilis, P. putida, P. fluorescens, and P. acidovorans) , Burkholderia (for example, B. pseudomallei, B. cepacia, B. cepacia complex, B. dolosa, B. fungorum, B. gladioli, B. multivorans, B. vietnamiensis, B. pseudomallei, B. ambifaria, B. andropogonis , B. anthina, B. brasilensis, B. caledonica, B. caribensis, B. caryophylli), Staphylococcus (e.g., S. aureus, S. auricularis, S. carnosus, S. epidermidis, S. lugdunensis), Staphylococcus aureusresistente to methicillin (MRSA), Streptococcus (for example, Streptococcus pneumoniae), Escherichia coli, Klebsiella, Enterobacter, Serratia, Haemophilus, Yersinia pestis, Mycobacterium (for example, non-tuberculous mycobacteria).
[00040] In one embodiment, the patient is treated for a pulmonary infection by non-tuberculous mycobacteria with one of the systems provided in this document. In another embodiment, pulmonary infection by non-tuberculous mycobacteria is a recalcitrant pulmonary infection by non-tuberculous mycobacteria.
[00041] In one embodiment, the systems provided in this document are used to treat a patient with a lung infection caused by Pseudomonas. In another embodiment, pulmonary infection is caused by a species of Pseudomonasselected from a species provided in Table B, below.


[00042] Pulmonary infection by non-tuberculous mycobacteria, in one modality is 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. intracellular e), 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 chelonae) or a combination thereof. In another modality, pulmonary infection by non-tuberculous mycobacteria is M. abscessus or M. avium. In another modality, infection by M. avium is M. avium subsp. hominissuis. In one embodiment, pulmonary infection by non-tuberculous mycobacteria is a recalcitrant lung infection by non-tuberculous mycobacteria.
[00043] In another embodiment, a patient with cystic fibrosis is treated for a bacterial infection with one of the systems provided in this document. In another embodiment, the bacterial infection is a pulmonary infection by Pseudomonas aeruginosa. In yet another modality, the patient is treated for a pulmonary infection associated with bronchiectasis with one of the systems provided in this document.
[00044] The term "prophylaxis", as used in this document, can mean the complete prevention of an infection or disease, or the prevention of the development of symptoms of that infection or disease; a delay in the onset of an infection or disease or its symptoms; or a decrease in the severity of a subsequently developed infection or illness or its symptoms.
[00045] The term "antibacterial" is recognized in the art and refers to the ability of the compounds of the present invention to prevent, inhibit or destroy the growth of bacteria microbes. Examples of bacteria are provided above.
[00046] The term "antimicrobial (o)" is recognized 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 microbes, such as bacteria, fungi, protozoa and viruses.
[00047] "Effective amount" means an amount of an aminoglycoside (e.g., amikacin) used in the present invention that is sufficient to result in the desired therapeutic response. The effective amount of the formulation provided in this document comprises both aminoglycoside complexed to the liposome and free. For example, the aminoglycoside complexed to the liposome, in one embodiment, comprises aminoglycoside encapsulated in a liposome, or complexed with a liposome, or a combination thereof.
[00048] In one embodiment, the aminoglycoside is selected from amikacin, apramycin, arbecacin, astromycin, capreomycin, dibecacin, framicetin, gentamicin, hygromycin B, isepamycin, kanamycin, neomycin, netylmycin, paromomycin, rodestreptomycin, ribostamycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin. , tobramycin or verdamycin. In another embodiment, the aminoglycoside is selected from an aminoglycoside shown in Table C below.

[00049] In one embodiment, aminoglycoside is a free base of aminoglycoside, or its salt, solvate or other non-covalent derivative. In another modality, the aminoglycoside is amikacin. Included as suitable aminoglycosides used in the drug formulations of the present invention are the pharmaceutically acceptable addition drug salts and complexes. In cases where the compounds may have one or more chiral centers, unless specified, the present invention comprises each unique racemic compound, as well as each unique non-racemic compound. In cases where the active agents have unsaturated carbon-carbon double bonds, both cis (Z) and trans (E) isomers are within the scope of the present invention. In cases where the active agents exist in tautomeric forms, such as ketoenol tautomers, each tautomeric form is contemplated to be within the scope of the invention. Amikacin, in one embodiment, is present in the pharmaceutical formulation as base amikacin, or amikacin salt, for example, amikacin sulfate or amikacin disulfate. In one embodiment, a combination of one or more of the above aminoglycosides is used in the formulations, systems and methods described in this document. In another embodiment, the combination comprises amikacin.
[00050] The therapeutic response can be any response that a user (for example, a doctor) will recognize as an effective response to therapy. The therapeutic response will generally be a reduction, inhibition, delay or prevention in the growth or reproduction of one or more bacteria, or the death of one or more bacteria, as described above. The therapeutic response can also be reflected in an improvement in lung function, for example, in forced expiratory volume in one second (FEVi). Still within the knowledge of one skilled in the art is the determination of the appropriate duration of a treatment, appropriate doses and any potential combination treatments, based on the assessment of the therapeutic response.
[00051] The term "liposomal dispersion" refers to a solution or suspension comprising a plurality of liposomes.
[00052] An "aerosol", as used herein, is a gas suspension of liquid particles. The aerosol provided in this document comprises particles of the liposomal dispersion.
[00053] A "nebulizer" or an "aerosol generator" is a device that converts a liquid into an aerosol of a size that can be inhaled through the respiratory tract. Pneumatic, ultrasonic, electronic nebulizers, for example, passive electronic mesh nebulizers, active electronic mesh nebulizers and vibration mesh nebulizers are liable to be used with the invention, if the particular nebulizer emits an aerosol with the required properties, at the rate income required.
[00054] The process of pneumatic conversion of a liquid into volume and droplets is called atomization. The operation of a pneumatic nebulizer requires a supply of pressurized gas as the driving force for liquid atomization. Ultrasonic nebulizers employ electricity introduced by a piezoelectric element into the liquid reservoir to convert a liquid into breathable droplets. Various types of nebulizers are described in Respiratory Care, Vol. 45, No. 6, pp. 609-622 (2000), the disclosure being incorporated into this document as a reference in its entirety. The terms "nebulizer" and "aerosol generator" are used interchangeably throughout the specification. "Inhalation device", "inhalation system" and "atomizer" are also used in the literature interchangeably with the terms "nebulizer" and "aerosol generator".
[00055] "Fine particle fraction" or "FPF", as used herein, refers to the fraction of the aerosol having a particle size of less than 5 pm in diameter, as measured by cascade impact. FPF is usually expressed as a percentage.
[00056] The term "mass average diameter" or "MMD" is determined by laser diffraction or by impactor measurements, and is the average diameter of the particles by weight.
[00057] The term "mass mean aerodynamic diameter" or "MMAD" is standardized in relation to the aerodynamic separation of aerosol droplets from water and is determined by impactor measurements, for example, the Andersen Cascade Impactor (ACI) or Next Generation Impactor (NGI). The gas flow, in one modality, is 28 liters per minute by the Andersen Cascade Impactor (ACI) and 15 liters per minute by the Next Generation Impactor (NGI). "Geometric standard deviation" or "GSD" is a measure of the dispersion of an aerodynamic particle size distribution.
[00058] In one embodiment, the present invention provides a system for treating a pulmonary infection or providing prophylaxis against pulmonary infection. The treatment is obtained by releasing the aminoglycoside formulation by inhalation through nebulization. In one embodiment, the pharmaceutical formulation comprises an aminoglycoside agent, for example, an aminoglycoside.
[00059] The pharmaceutical formulation as provided herein is a liposomal dispersion. Specifically, the pharmaceutical formulation is a dispersion that comprises an "aminoglycoside complexed with a liposome" or an "aminoglycoside encapsulated in a liposome". A "liposome complexed aminoglycoside" includes modalities in which the aminoglycoside (or combination of aminoglycosides) is encapsulated in a liposome and includes any form of aminoglycoside composition in which at least about 1% by weight of the aminoglycoside is associated with the liposome either as part of a complex with a liposome, or as a liposome in which the aminoglycoside can be in the aqueous or hydrophobic bilayer phase or in the interfacial head group region of the liposomal bilayer.
[00060] In one embodiment, the lipid component of the liposome comprises electrically neutral lipids, positively charged lipids, negatively charged lipids, or a combination thereof. In another embodiment, the lipid component comprises electrically neutral lipids. In another embodiment, the lipid component consists essentially of electrically neutral lipids. In yet another embodiment, the lipid component consists of electrically neutral lipids, for example, a sterol and a phospholipid.
[00061] As stated above, modalities of complexed liposome aminoglycosides include modalities in which the aminoglycoside is encapsulated in a liposome. In addition, the aminoglycoside complexed to the liposome describes any composition, solution or suspension in which at least about 1% by weight of the aminoglycoside is associated with the lipid, either as part of a complex with the liposome, or as a liposome in which the aminoglycoside can be in the aqueous phase or hydrophobic bilayer phase or in the region of the interfacial head group of the liposomal bilayer. In one embodiment, before 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 formulation are associated. The association, in one embodiment, is measured by separation by means of a filter, where lipid and drug associated with the lipid are retained (that is, in the retentate) and the free drug is in the filtrate.
[00062] The formulations, systems and methods provided herein comprise an aminoglycoside agent encapsulated in the lipid or associated with the lipid. The lipids used in the pharmaceutical formulations of the present invention can be synthetic, semi-synthetic or naturally occurring lipids, including phospholipids, tocopherols, sterols, fatty acids, negatively charged lipids and cationic lipids.
[00063] In one embodiment, at least one phospholipid is present in the pharmaceutical formulation. In one embodiment, the phospholipid is selected from: phosphatidylcholine (EPC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE) and phosphatidic acid (PA); the counterparts of soy, soy phosphatidylcholine (SPC); SPG, SPS, SPI, SPE and SPA; hydrogenated and soybean counterparts (eg, HEPC, HSPC), phospholipids consisting of fatty acid ester chains in positions 2 and 3 of glycerol, containing chains of positions from 12 to 26 carbon atoms and different head groups in the position 1 glycerol which includes choline, glycerol, inositol, serine, ethanolamine, as well as the corresponding phosphatidic acids. The carbon chains on these fatty acids can be saturated or unsaturated and the phospholipid can consist of fatty acids of different chain lengths and different degrees of unsaturation.
[00064] In one embodiment, the pharmaceutical formulation comprises dipalmitoylphosphatidylcholine (DPPC), one of the main constituents of the naturally occurring pulmonary surfactant. In one embodiment, the lipid component of the pharmaceutical formulation comprises DPPC and cholesterol, or consists essentially of DPPC and cholesterol or consists of DPPC and cholesterol. In another embodiment, DPPC and cholesterol have a molar ratio in the range of about 19: 1 to about 1: 1, or about 9: 1 to about 1: 1, or about 4: 1 to about from 1: 1, or about 2: 1 to about 1: 1, or about 1.86: 1 to about 1: 1. In yet another embodiment, DPPC and cholesterol have a molar ratio of about 2: 1 or about 1: 1. In one embodiment, DPPC and cholesterol are supplied in an aminoglycoside formulation.
[00065] Other examples of lipids for use with the invention include, but are not limited to, dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylglycerol (DS) ethanolamine (DOPE), mixed phospholipids such as palmitoylstearoylphosphatidylcholine (PSPC) and simple acylated phospholipids, for example mono-oleoyl phosphatidylethanolamine (MOPE).
[00066] In one embodiment, the at least one lipid component comprises a sterol. In another embodiment, the component of at least one lipid comprises a sterol and a phospholipid, or consists essentially of a sterol and a phospholipid, or consists of a sterol and a phospholipid. Sterols for use with the invention include, but are not limited to cholesterol, cholesterol esters including cholesterol hemisuccinate, cholesterol salts including hydrogenated cholesterol sulfate and cholesterol sulfate, ergosterol, ergosterol esters including ergosterol hemisuccinate, ergosterol salts including ergosterol sulfate and hydrogenated ergosterol sulfate, lanosterol, lanosterol esters including lanosterol hemisuccinate, lanosterol salts including hydrogenated lanosterol sulfate, lanosterol sulfate and tocopherols. Tocopherols can include tocopherols, tocopherol esters, including hemisuccinate tocopherols, tocopherols, including salts of hydrogenated tocopherol sulphates and tocopherol sulphates. The term "sterol compound" includes sterols, tocopherols and the like.
[00067] In one embodiment, at least one cationic lipid (positively charged lipid) is supplied to the systems described in this document. The cationic lipids used can include ammonium salts of fatty acids, phospholides and glycerides. Fatty acids include fatty acids of carbon chain lengths of 12 to 26 carbon atoms, which are either saturated or unsaturated. Some specific examples include: myristylamine, palmitilamine, laurylamine and stearylamine, dilauroyl ethylphosphocholine (DLEP), dimyristoyl ethylphosphocholine (DMEP), dipalmitoyl ethylphosphocholine (DPEP) and distearoyl ethylphosphocholine (DSEP), N-2,3-chloride (9- (Z) - octadecenyloxy) -prop-1-yl-N, N, N-trimethylammonium (DOTMA) and 1,2-bis (oleoyloxy) -3- (trimethylammonium) propane (DOTAP).
[00068] In one embodiment, at least one anionic lipid (negatively charged lipid) is supplied to the systems described in this document. Negatively charged lipids that can be used include phosphatidyl glycerols (PGs), phosphatidic acids (PAs), phosphatidylinositols (Pis) and phosphatidylcholine serines (PSs). Examples include DMPG, DPPG, DSPG, DMPA, DPPA, DSPA, DMPI, DPPI, DSPI, DMPS, DPPS and DSPS.
[00069] Without being bound by theory, phosphatidylcholines, such as DPPC, aid in the absorption of the aminoglycoside agent by cells in the lung (for example, alveolar macrophages) and help to maintain the aminoglycoside agent in the lung. It is believed that negatively charged lipids, such as PGs, PAs, PSs and Pis, in addition to reducing particle aggregation, play a role in the prolonged activity characteristics of the inhalation formulation, as well as in the transport of the formulation through the lung. (transcitosis) for systemic absorption. It is believed that sterol compounds, without claiming to be limited by theory, affect the release characteristics of the formulation.
[00070] Liposomes are completely closed lipid bilayer membranes containing a trapped aqueous volume. Liposomes can be unilamellar vesicles (having a single bilayer membrane) or multilamellar vesicles (onion-like structures, characterized by multiple bilayer membranes, each separated from the next by an aqueous layer) or a combination thereof. The bilayer is composed of two lipid monolayers having a hydrophobic "tail" and a hydrophilic "head" region. The structure of the bilayer membrane is such that the hydrophobic (backing) "tails" of the lipid monolayers are oriented towards the center of the bilayer while the hydrophilic "heads" are oriented towards the aqueous phase.
[00071] Liposomes can be produced by a variety of methods (see, for example, Cullis et al. (1987)). In one embodiment, one or more of the methods described in US Patent Application Publication Number 2008/0089927 are used herein to produce the lipid formulations of encapsulated aminoglycoside (liposomal dispersion). The disclosure of US Patent Application Publication Number 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 form the liposome formulation. The coacervate can be formed before mixing with the lipid, during mixing with the lipid, or after mixing with the lipid. In addition, the coacervate can be a coacervate of the active agent.
[00072] In one embodiment, the dispersion of liposomes is formed by dissolving one or more lipids in an organic solvent, forming a lipid solution, and the aminoglycoside coacervate is formed by mixing an aqueous solution of the aminoglycoside with the lipid solution . In another embodiment, the organic solvent is ethanol. In yet another embodiment, the one or more lipids comprise a phospholipid and a sterol.
[00073] In one embodiment, liposomes are produced by sonication, extrusion, homogenization, swelling, electroforming, inverted emulsion or a reverse evaporation method. The Bangham procedure (J. Mol. Biol. (1965)) produces common multilamellar vesicles (MLVs). Lenk et al. (US patent number 4,522,803, 5,030,453 and 5,169,637), Fountain et al. (US patent number 4,588,578) and Cullis and others (US patent number 4,975,282) disclose methods for producing multilamellar liposomes having interlayer distribution of substantially equal solute in each of its aqueous compartments. Paphadjopoulos et al., US Patent No. 4,235,871, discloses the preparation of oligolamellar liposomes by reverse phase evaporation. Each method is favorable for use with the present invention.
[00074] Unilamellar vesicles can be produced from MLVs by a series of techniques, for example, the extrusion techniques of US Patent Number 5,008,050 and US Patent Number 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)).
[00075] The preparation of liposomes from Bangham et al. (J. Mol. Biol. 13, 1965, pp. 238-252) involves the suspension of phospholipids in an organic solvent which is then evaporated to dryness leaving a phospholipid film in the reaction vessel. Then, an appropriate amount of aqueous phase is added, the mixture is allowed to "swell" and the resulting liposomes that are made up of multilamellar vesicles (MLVs) are dispersed by mechanical means. This preparation provides the basis for the development of small sonicated unilamellar vesicles described by Papahadjopoulos et al. (Biochim. Biophys. Acta. 135, 1967, pp. 624-638), and of large unilamellar vesicles.
[00076] Techniques for the production of large unilamellar vesicles (LUVs), such as, reverse phase evaporation, infusion procedures and detergent dilution can be used to produce the liposomes for use in the pharmaceutical formulations provided herein. A review of these and other methods for the production of liposomes can be found in the text Liposomes, Marc Ostro, ed., Marcel Dekker, Inc., New York, 1983, Chapter 1, which is incorporated into this document by reference. See also Szoka, Jr. and others, (Ann. Rev. Biophys. Bioeng. 9, 1980, p. 467), which is also incorporated into this document as a reference in its entirety for all purposes.
[00077] Other techniques for the preparation of liposomes include those that form reverse phase evaporation (REV) vesicles, US Patent No. 4,235,871. Another class of liposomes that can be used is characterized by having a substantially equal distribution of lamellar solute. This class of liposomes is referred to as stable plurilamellar vesicles (SPLV), as defined in US Patent No. 4,522,803, and includes monophasic vesicles as described in US Patent 4,588,578, and frozen and thawed multilamellar vesicles (FATMLV), as described above.
[00078] A variety of sterols and their water-soluble derivatives, such as cholesterol hemisuccinate have been used to form liposomes; see, for example, US Patent Number 4,721,612. Mayhew et al., PCT Publication Number WO 85/00968, described a method for reducing the toxicity of drugs, encapsulating them in liposomes comprising alpha-tocopherol and some of its derivatives. In addition, a variety of tocopherols and their water-soluble derivatives have been used to form liposomes, see PCT Publication Number 87/02219.
[00079] The pharmaceutical formulation, in one embodiment, pre-nebulization, comprises liposomes with an average diameter that is measured by a light scattering method, from about 0.01 pm to about 3.0 pm, for example , in the range of about 0.2 to about 1.0 pm. In one embodiment, the average diameter of the liposomes in the formulation is about 200 nm to about 300 nm, about 210 nm to about 290 nm, about 220 nm to about 280 nm, from about 230 nm to about 280 nm, 240 nm to about 280 nm, about 250 nm to about 280 nm or about 260 nm to about 280 nm. The profile of prolonged activity of the liposomal product can be regulated by the nature of the lipid membrane and by the inclusion of other excipients in the composition.
[00080] In order to minimize the dose volume and reduce the dosage time of the patient, in one embodiment, it is important that the liposomal trapping of the aminoglycoside (for example, the aminoglycoside amikacin) is highly efficient and that the L / D ratio is as low as possible and / or practical, keeping the liposomes small enough to penetrate the patient's mucus and biofilms, for example, Pseudomonas biofilms. In one embodiment, the L / D ratio in the liposomes provided in this document is 0.7 or about 0.7 (weight / weight). In another embodiment, the liposomes provided in this document are small enough to effectively penetrate a bacterial biofilm (for example, Pseudomonas biofilm). In yet another embodiment, the average diameter of the liposomes, as measured by light scattering, is about 260 to about 280 nm.
[00081] The drug-to-lipid ratio in pharmaceutical formulations provided in an embodiment herein is 3 to 1 or less, 2.5 to 1 or less, 2 to 1 or less, 1.5 to 1 or less, or from 1 to 1 or less. The lipid-to-drug ratio in pharmaceutical formulations provided in another embodiment herein is less than 3 to 1, less than 2.5 to 1, less than 2 to 1, less than 1.5 to 1, or less than 1 to 1. In another embodiment, the lipid to drug ratio is about 0.7 or less or about 0.7 to 1. In one embodiment, one of the lipids or combinations of lipids in Table 1, below, is used in pharmaceutical formulation of the invention.

[00082] In one embodiment, the system provided in this document comprises an aminoglycoside formulation, for example, an amikacin formulation, for example, amikacin-based formulation. In one embodiment, the amount of aminoglycoside supplied in the system 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 supplied in the system 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 about from 550 mg to about 600 mg. In one embodiment, the amount of aminoglycoside administered to the individual is about 560 mg and is supplied in an 8 ml formulation. In one embodiment, the amount of aminoglycoside administered to the individual is about 590 mg and is supplied in an 8 ml formulation. In one embodiment, the amount of aminoglycoside administered to the individual is about 600 mg and is supplied in an 8 mL formulation. In one embodiment, the aminoglycoside is amikacin and the amount of amikacin supplied in the system 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 supplied to the system 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 individual is about 560 mg, and is supplied in an 8 ml formulation. In one embodiment, the aminoglycoside is amikacin and the amount of amikacin administered to the individual is about 590 mg, and is supplied in an 8 ml formulation. In one embodiment, the aminoglycoside is amikacin and the amount of aminoglycoside administered to the individual is about 600 mg and is supplied in an 8 ml formulation.
[00083] In one embodiment, the system provided in this document comprises an aminoglycoside formulation, for example, an amikacin (base formulation). In one embodiment, the aminoglycoside formulation provided herein comprises 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 another modality, the aminoglycoside is amikacin.
[00084] In one embodiment, the system provided in this document comprises a liposomal amikacin formulation of about 8 ml. In one embodiment, the density of the liposomal amikacin formulation is about 1.05 g / ml; and in one embodiment, approximately 8.4 grams of the liposomal amikacin formulation per dose is present in the system of the invention. In another embodiment, the entire volume of the formulation is administered to an individual who needs it.
[00085] In one embodiment, the pharmaceutical formulation provided in this document comprises at least one aminoglycoside, at least one phospholipid and a sterol. In another embodiment, the pharmaceutical formulation comprises an aminoglycoside, DPPC and cholesterol. In one embodiment, the pharmaceutical formulation is the formulation provided in Table 2, below.


[00086] It should be noted that increasing the concentration of aminoglycoside alone may not result in a reduced dosing time. For example, in one embodiment, the lipid-to-drug ratio is fixed, and as the concentration of amikacin is increased (and therefore the lipid concentration is increased, since the ratio between the two is fixed, for example, ~ 0.7: l), the viscosity of the solution also increases, which decreases the nebulization time.
[00087] In one embodiment, before nebulization of the aminoglycoside formulation, about 70% to about 100% of the aminoglycoside present in the formulation is complexed to the liposome. In another embodiment, the aminoglycoside is an aminoglycoside. In yet another modality, the aminoglycoside is amikacin. In another embodiment, before 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 formulation is complexed with the liposome. In another embodiment, the aminoglycoside is amikacin or tobramycin. In yet another modality, the aminoglycoside is amikacin. In another embodiment, before nebulization, about 98% of the aminoglycoside present in the formulation is complexed with the liposome. In another embodiment, the aminoglycoside is amikacin or tobramycin. In yet another modality, the aminoglycoside is amikacin.
[00088] In an embodiment when nebulization about 20% to about 50% of the aminoglycoside agent complexed to the liposome are released, due to the shear stress on the liposomes. In another embodiment the agent is an amikacin aminoglycoside. In another embodiment, by nebulization about 25% to about 45%, or about 30% to about 40% of the aminoglycoside agent complexed to the liposome are released, due to the shear stress in the liposomes. In another embodiment, the aminoglycoside agent is amikacin.
[00089] As provided herein, the present invention provides methods and systems for the treatment of pulmonary infections by inhalation of a liposomal aminoglycoside formulation by nebulization. The formulation, in one embodiment, is administered through a nebulizer, which provides an aerosol mist of the formulation for distribution to an individual's lungs.
[00090] In one embodiment, the nebulizer described in this document generates an aerosol (that is, it achieves a total yield rate) of the aminoglycoside pharmaceutical formulation at a rate greater than about 0.53 g / min., Greater than about 0.54 g / min., greater than about 0.55 g / min., greater than about 0.58 g / min., greater than about 0.60 g / min., greater than about 0 , 65 g / min. or greater than about 0.70 g / min. In yet another embodiment, the nebulizer described in this document generates an aerosol (that is, it achieves a total yield rate) of the aminoglycoside pharmaceutical formulation at about 0.53 g / min. at about 0.80 g / min., at about 0.53 g / min. to about 0.70 g / min. , about 0.55 g / min. to about 0.70 g / min., about 0.53 g / min. to about 0.65 g / min, or about 0.60 g / min. to about 0.70 g / min. In yet another embodiment, the nebulizer described in this document generates an aerosol (that is, it achieves a total yield rate) of the pharmaceutical aminoglycoside formulation of about 0.53 g / min. at about 0.75 g / min, about 0.55 g / min. at about 0.75 g / min., about 0.53 g / min. to about 0.65 g / min, or about 0.60 g / min. to about 0.75 g / min.
[00091] After nebulization, liposomes leak the drug into the pharmaceutical formulation. In one embodiment, the amount of aminoglycoside complexed to the post-nebulized liposome is about 45% to about 85%, or about 50% to about 80% or about 51% to about 77%. These percentages are also referred to in this document as "percentage associated with post-nebulization of aminoglycoside". As provided herein in an embodiment, liposomes comprise an aminoglycoside, for example, amikacin. In one embodiment, the associated percentage of aminoglycoside after nebulization is about 60% to about 70%. In another modality, the aminoglycoside is amikacin. In another modality, the associated percentage of aminoglycoside after nebulization is about 67%, or about 65% to about 70%. In another modality, the aminoglycoside is amikacin.
[00092] In one embodiment, the associated percentage of aminoglycoside after nebulization is measured with the recovery of aerosol from the air by condensation in a cold siphon, and the liquid is subsequently tested for free and encapsulated aminoglycoside (associated aminoglycoside) .
[00093] In one embodiment, the MMAD of the aerosol of the pharmaceutical formulation is less than 4.9 pm, less than 4.5 pm, less than 4.3 pm, less than 4.2 pm, less than 4.1 pm, less than 4.0 pm, or less than 3.5 pm, as measured by ACI, at a gas flow rate of about 28 L / minute, or by the Next Generation Impactor NGI at a gas flow rate of about 15 L /minute.
[00094] In one embodiment, the MMAD of the aerosol of the pharmaceutical formulation is about 1.0 pm to about 4.2 pm, about 3.2 pm, to about 4.2 pm, about 3.4 pm to about 4.0 pm, about 3.5 pm to about 4.0 pm or about 3.5 pm to about 4.2 pm, as measured by ACI. In one embodiment, the MMAD of the aerosol of the pharmaceutical formulation is from about 2.0 pm to about 4.9 pm, about 4.4 pm to about 4.9 pm, about 4.5 pm to about 4.9 pm, or about 4.6 pm to about 4.9 pm, as measured by NGI.
[00095] In another embodiment, the nebulizer described in this document generates an aerosol pharmaceutical formulation of aminoglycoside at a rate greater than about 0.53 g / min., Greater than about 0.55 g / min., Or greater at about 0.60 g / min. or about 0.60 g / min. at about 0.70 g / min. In another embodiment, the FPF of the aerosol is greater than or equal to about 64%, as measured by ACI, greater than or equal to about 70%, as measured by ACI, greater than or equal to about 51% , measured by NGI, or greater than or equal to about 60%, as measured by NGI.
[00096] In one embodiment, the system provided in this document comprises a nebulizer selected from an electronic mesh nebulizer, a pneumatic nebulizer (jet), an ultrasound nebulizer, a nebulizer capable of breathing and a nebulizer activated by breathing. In one embodiment, the nebulizer is portable.
[00097] The principle of operation of a pneumatic nebulizer is generally known to those skilled in the art and is described, for example, in Respiratory Care, Vol. 45, No. 6, pp. 609-622 (2000). Briefly, a source of pressurized gas is used as the driving force for the atomization of liquid in a pneumatic nebulizer. The compressed gas is released, which causes a region of negative pressure. The solution to be aerosolized is then released into the gas stream and cut into a liquid film. This film is unstable and breaks into droplets due to forces of surface tension. The smaller particles, that is, particles with MMAD properties described above and FPF, can then be formed by placing a deflector in the aerosol stream. In a modality of pneumatic nebulizer, gas and solution are mixed before leaving the outlet opening (nozzle) and interact with the deflector. In another embodiment, mixing will not take place until the liquid and gas leave the outlet (nozzle). In one embodiment, the gas is air, O2 and / or CO2.
[00098] In one embodiment, the droplet size and yield rate can be adapted in a pneumatic nebulizer. However, attention should be paid to the formulation to be nebulized and whether the properties of the formulation (for example,% of associated aminoglycoside) are changed due to modification of the nebulizer. For example, in one embodiment, the gas rate and / or the rate of the pharmaceutical formulation is modified to achieve the droplet sizes and yield rate of the present invention. Additionally or alternatively, the flow rate of the gas and / or solution can be adjusted to obtain the droplet size and yield rate of the invention. For example, an increase in gas velocity, in one embodiment, decreases the size of the droplets. In one embodiment, the flow rate of the pharmaceutical formulation to the gas flow is adjusted to obtain the droplet size and yield rate of the invention. In one embodiment, an increase in the ratio of liquid to gas flow increases the particle size.
[00099] In one embodiment, a rate of performance of the pneumatic nebulizer is increased by increasing the filling volume in the liquid reservoir. Without wishing to be limited by theory, the increase in the yield rate may be due to a reduction in the dead volume in the nebulizer. The nebulization time, in one mode, is reduced, increasing the flow to feed the nebulizer. See, for example, Clay et al. (1983). Lancet 2, pp. 592-594 and Hess et al. (1996). Chest 110, pp. 498-505.
[000100] In one embodiment, a reservoir bag is used to capture aerosol during the nebulization process, and the aerosol is subsequently supplied to the individual via inhalation. In another embodiment, the nebulizer provided in this document includes an open tube vent design. In this mode, when the patient inhales through the nebulizer, the output of the nebulizer is increased. During the expiration phase, a one-way valve diverts the patient's flow out of the nebulizer chamber.
[000101] In one embodiment, the nebulizer provided in this document is a continuous nebulizer. In other words, refilling the nebulizer with the pharmaceutical formulation, while administering a dose is not necessary. Instead, the nebulizer has at least an 8 ml capacity or at least a 10 ml capacity.
[000102] In one embodiment, a vibrating mesh nebulizer is used to deliver the aminoglycoside formulation of the invention to a patient in need thereof. In one embodiment, the nebulizer membrane vibrates at an ultrasonic frequency of about 100 kHz to about 250 kHz, about 1 to about 10 kHz to 200 kHz, from about 1 to about 10 kHz to 200 kHz, from about 1 to about 10 kHz to 150 kHz. In one embodiment, the nebulizer membrane vibrates at a frequency of about 117 kHz by applying an electric current.
[000103] In one embodiment, the nebulizer provided in this document does not use an air compressor and, therefore, does not generate an air flow. In one embodiment, the aerosol is produced by the aerosol head that enters the mixing chamber of the device. When the patient inhales, air enters the mixing chamber via one-way inhalation valves at the back of the mixing chamber and carries the aerosol through the mouthpiece to the patient. On exhalation, the patient's breath flows through the one-way exhalation valve at the mouthpiece of the device. In one embodiment, the nebulizer continues to generate aerosol in the mixing chamber which is then aspirated by the individual on the next breath and this cycle continues until the nebulizer medicine reservoir is empty.
[000104] Although not limited to this, the present invention in one embodiment is carried out with one of the aerosol generators (nebulizers) represented in Figures 1, 2, 3 and 4. In addition, the systems of the invention, in one embodiment include a nebulizer described in European Patent Applications 11169080.6 and / or 10192385.2. These orders are incorporated as a reference in their entirety.
[000105] Figure 1 shows a therapeutic aerosol device 1 with a nebulizer chamber 2, a nozzle 3 and an aerosol generator 4 with an oscillating membrane 5. The oscillating membrane can, for example, be oscillated by piezo elements annular (not shown), examples of which are described in WO 1997/29851.
[000106] When in use, the pharmaceutical formulation is located on one side of the oscillating membrane 5, see figures 1, 2 and 4, and this liquid is then transported through openings in the oscillating membrane 5 and emitted on the other side of the oscillating membrane 5, see the lower part of Figure 1, Figure 2, as an aerosol into the nebulizer chamber 2. The patient is able to breathe the aerosol present in the nebulizer chamber 2 in the mouthpiece 3.
[000107] The oscillating membrane 5 comprises a plurality of through-holes. Goticulas from the aminoglycoside formulation are generated when the pharmaceutical aminoglycoside formulation passes through the membrane. In one embodiment, the membrane is vibrating, a so-called active electronic mesh nebulizer, for example, the PARI Pharma eFlow® nebulizer, Health and Life's HL100 or Aerogen's Aeroneb Go® (Novartis). In another embodiment, the membrane vibrates at an ultrasonic frequency of about 100 kHz to about 150 kHz, about 110 kHz to about 140 kHz, or about 110 kHz to about 120 kHz. In another embodiment, the membrane vibrates at a frequency of about 117 kHz by applying an electric current. In another embodiment, the membrane is fixed and another part of the fluid reservoir or fluid supply is vibrating, a so-called passive electronic mesh nebulizer, for example, the Omron MicroAir Model U22 electronic nebulizer or the Inhalation System I-Neb I-neb AAD from Philips Respironics.
[000108] In one embodiment, the length of the nozzle portion of the through holes formed in the membrane (for example, vibrating membrane) influences the total yield rate (RPT) of the aerosol generator. In particular, it was found that the length of the nozzle portion is directly proportional to the total yield rate, in which the shorter the nozzle portion, the greater the TOR and vice versa.
[000109] In one embodiment, the nozzle portion is sufficiently short and small in diameter compared to the upstream portion of the through hole. In another embodiment, the length of the portions upstream of the nozzle portion within the through hole has no significant influence on the TOR.
[000110] In one embodiment, the length of the nozzle portion influences the geometric standard deviation (GSD) of the droplet size distribution of the aminoglycoside pharmaceutical formulation. Low GSDs characterize a narrow droplet size distribution (homogeneously sized droplets), which is advantageous for directing the aerosol to the respiratory system, for example, for the treatment of bacterial infections (eg, Pseudomonasou Mycobacteria) in patients with cystic fibrosis, or the treatment of non-tuberculous mycobacteria, bronchiectasis (for example, treatment of cystic fibrosis or patients without cystic fibrosis), Pseudomonasor Mycobacteria in patients. That is, the longer the nozzle portion, the smaller the GSD. The average droplet size, in one embodiment, is less than 5 pm, and has a GSD in the range of 1.0 to 2.2, or about 1.0 to about 2.2, or 1.5- 2.2, or about 1.5 to about 2.2.
[000111] In one embodiment, as indicated above, the system provided in this document comprises a nebulizer that generates an aerosol of the pharmaceutical formulation of aminoglycoside at a rate greater than about 0.53 g / min., Or greater than about 0 , 55 g / min. In another embodiment, the nebulizer comprises a vibrating membrane having a first side in contact with the fluid and a second opposite side, from which the droplets emerge.
[000112] The membrane, for example, a stainless steel membrane, can be vibrated by means of a piezoelectric actuator or any other suitable means. The membrane has a plurality of penetration holes through the membrane in an extension direction from the first side to the second side. The through holes can be formed as previously mentioned by a laser source, electrodeposition or any other suitable process. When the membrane is vibrating, the aminoglycoside pharmaceutical formulation passes through the holes on the first side to the second side in order to generate the aerosol on the second side. Each of the through-holes, in one embodiment, comprises an entrance opening and an exit opening. In another embodiment, each of the through holes comprises a nozzle portion extending from the outlet opening along a portion of the through holes towards the inlet opening. The nozzle portion is defined by the continuous portion of the through hole in the direction of the extension which comprises a smaller diameter of the through hole and limited by a larger diameter of the through hole. In one embodiment, the largest diameter of the through hole which is defined as the diameter that is closest to 3 times, about 3 times, 2 times, about 2 times, 1.5 times, or about 1.5 times the smaller diameter.
[000113] The smallest diameter of the through hole, in one embodiment, is the diameter of the outlet opening. In another embodiment, the smallest diameter of the through hole is about 0.5x, about 0.6x, and about 0.7x, about 0.8x, or about 0.9 times the diameter the exit opening.
[000114] In one embodiment, the nebulizer provided in this document comprises through holes in which the ratio between the total length of at least one of the through holes in the direction of extension to the length of the respective nozzle portion of the through hole in the extension direction is at least 4, or at least about 4, or at least 4.5, or at least about 4.5, or at least 5, or at least about 5, or greater than about 5. In another embodiment, the nebulizer provided in this document comprises through-holes in which the relationship between the total length of most through-holes in the direction of extension to the length of the respective nozzle portion of the through-holes in the direction the length is at least 4, or at least about 4, or at least 4.5, or at least about 4.5, or at least 5, or at least about 5, or greater than about of 5.
[000115] The extension ratios set out above provide, in one embodiment, an increased total yield ratio compared to previously known nebulizers, and also provide a sufficient GSD. The proportion settings, in one modality, reach shorter application periods, leading to greater comfort for the patient and effectiveness of the aminoglycoside compound. This is particularly advantageous if the aminoglycoside compound in the formulation, due to its properties, is prepared in a low concentration, and therefore a larger volume of the aminoglycoside pharmaceutical formulation must be administered in an acceptable time, for example, one session. dosage.
[000116] According to one embodiment, the nozzle portion ends flush with the second side. Therefore, the length of the nozzle portion in one embodiment is defined as that portion starting on the second side towards the first side up to and limited by the diameter that is closest to about triple, about twice, about two and a half times or about one and a half times the smaller diameter. The smallest diameter in this mode is the diameter of the outlet opening.
[000117] In one embodiment, the smallest diameter (ie, a limit of the nozzle portion) is located at the end of the nozzle portion in the direction of extension adjacent to the second side. In one embodiment, the largest diameter of the through hole, located on the other edge of the nozzle portion, is located upstream of the smallest diameter in the direction in which the fluid passes the plurality of through holes during operation.
[000118] According to one embodiment, the smallest diameter is less than about 4.5 pm, less than about 4.0 pm, less than about 3.5 pm, or less than about 3.0 pm.
[000119] In one embodiment, the total length of at least one through hole in the direction of extension is at least about 50 pm, at least about 60 pm, at least about 70 pm, or at least least about 80 p m. In another embodiment, the total length of at least one of the plurality of through-holes is at least about 90 µm. In one embodiment, the total length of a majority of the plurality of through-holes in the extension direction is at least about 50 pm, at least about 60 pm, at least about 70 pm, or at least least about 80 pm. In another embodiment, the total length of a majority among the plurality of through-holes is at least about 90 pm.
[000120] The length of the mouthpiece portion, in one embodiment, is less than about 25 pm, less than about 20 pm or less than about 15 pm.
[000121] According to one embodiment, the through holes are laser-drilled through holes formed in at least two phases, one phase forming the laser-drilled nozzle zone and the remaining phase (s) forming the other through holes. passage.
[000122] In another embodiment, the manufacturing methods used lead to a nozzle portion that is substantially cylindrical or conical, with a tolerance of less than + 100% of the smallest diameter, less than + 75% of the smallest diameter, less than 50% of the smallest diameter, less than + 30% of the smallest diameter, less than + 25% of the smallest diameter, or less than + 15% of the smallest diameter.
[000123] Alternatively or additionally, the through holes are formed in an electroplating process. In one embodiment, the through holes have a first funnel-shaped portion on the first side and a second funnel-shaped portion on the second side, with the nozzle portion between the first and second portions and defined between the opening of the funnel-shaped outlet and larger diameter. In this example, the total length of the through holes can thus be defined by the distances from the first side to the outlet opening (smallest diameter) only.
[000124] In addition, the total yield rate (TOR) can be further increased by increasing the number of through holes provided in the membrane. In one embodiment, an increase in the number of through holes is achieved by increasing the active perforated surface of the membrane and maintaining the distance from the through holes in relation to the other at the same level. In another embodiment, the number of through holes is increased by reducing the distance from the through holes to each other and maintaining the active area of the membrane. In addition, a combination of the two previous strategies can be used.
[000125] In one embodiment, the total nebulizer yield rate described in this document is increased by increasing the density of holes in the membrane. In one embodiment, the average distance between the through-holes is about 70 pm or about 60 pm or about 50 pm.
[000126] In one embodiment, the membrane comprises between about 200 and about 8,000 through holes, between about 1,000 and about 6,000 through holes, between about 2,000 and about 5,000 through holes, or about 2,000 and about 4,000 through-holes. In one embodiment, the number of through-holes described above increases the TOR, and the TOR is increased, regardless of whether the mouthpiece parameters are implemented as described above. In one embodiment, the nebulizer provided in this document comprises about 3,000 through-holes. In another embodiment, the through holes are located in a hexagonal arrangement, for example, more or less in the center of the membrane (for example, stainless steel membrane). In another modality, the average distance between orifices is about 70 pm.
[000127] Figure 3 shows an aerosol generator (nebulizer) as disclosed in WO 2001/032246, which is incorporated into the document as a reference in its entirety. The aerosol generator comprises a fluid reservoir 21 to contain the pharmaceutical formulation, to be emitted into the mixing chamber 3 in the form of an aerosol and to be inhaled through the mouthpiece 4 through the opening 41.
[000128] The aerosol generator comprises a vibrating membrane 22 which vibrates by means of a piezoelectric driver 23. The vibrating membrane 22 has a first side 24 facing the fluid container 21 and a second opposite side 25 facing the mixing chamber 3. In use, the first side 24 of the vibrating membrane 22 is in contact with the fluid contained in the fluid container 21. Several through holes 26 that penetrate the membrane from the first side 24 to the second side 25 are provided in the membrane 22. In use, the fluid passes from the fluid container 21 through the through-holes 26 from the first 24 to the second side 25 when the membrane 22 vibrates to generate the aerosol on the second side 25 and emits it to the inside the mixing chamber 3. This aerosol can then be drained by inhaling a patient from the mixing chamber 3 via the mouthpiece part 4 and its inhalation opening 41.
[000129] Figure 5 shows a cross-sectional computed tomography showing three through holes 26 of such a vibrating membrane 22. The through holes 26 of the present specific embodiment are formed by laser drilling using three phases of different process parameters, respectively . In a first stage, part 30 is formed. In a second phase, the portion 31 is formed and in a third phase the nozzle portion 32 is formed. In this particular embodiment, the length of the nozzle portion 32 is about 26 pm, while the portion 31 has a length of about 51 pm. The first portion 30 has a length of about 24.5 µm. As a result, the total length of each through hole is the sum of the length of the portion 30, the portion 31 and the nozzle portion 32, which in this particular example is about 101.5 µm. Thus, the ratio of the total length of each through hole 26 in the direction of extension E to the length of one of the respective nozzle portions 32 in the direction of extension E is approximately 3.9.
[000130] In the embodiment of Figure 6, the first portion 30 has a length of about 27 pm, the portion 31 a length of about 55 pm and a mouthpiece portion a length of about 19 pm. As a result, the total length of hole 26 is about 101.5 µm. Thus, the ratio of the total length of the through hole 26 to the length of the corresponding nozzle portion 32 in this embodiment is approximately 5.3.
[000131] Both vibrating membranes in Figures 5 and 6 were manufactured with 6,000 through-holes 26. The table below (Table 3) indicates the average diameter in weight (MMD), as determined by laser diffraction, of the particles emitted in the second side of the membrane, the time required to completely emit a certain amount of liquid (nebulization time) as well as the TOR. The tests were performed with a liposomal formulation of amikacin.


[000132] Table 3 shows that membrane 2 with the smaller nozzle portion provides an increase in TOR and a reduction in nebulization time by 5.3 minutes, which is approximately 36% less compared to membrane 1. A Table 3 also shows that MMD did not vary significantly for each membrane tested. This contrasts with the differences observed in the TORs for each membrane. Thus, in one embodiment, the nebulization time for the nebulizer described in this document is significantly reduced, compared to nebulizers in the prior art, without affecting the droplet size, as measured by MMD.
[000133] In addition to the membrane shown in Figures 5 and 6, the membranes were manufactured having the nozzle portion even smaller, and with 3,000 through-holes 26 (membranes 3 and 4, Table 3). In particular, a membrane 3 was laser drilled with a shorter nozzle portion, whereas membrane 4 was manufactured using a shorter nozzle portion than membrane 3. Table 3 shows that, even with 3,000 holes (membranes 3 and 4) a reduction in the length of the nozzle portion results in an increase in TOR compared to a 6,000 hole membrane. The comparison between membrane 3 and 4, compared to membrane 2 further shows that a combination of a larger number of orifices (6,000 compared to 3,000) and a reduced length of the nozzle portion increases the TOR for the nebulizer.
[000134] In one embodiment, it is advantageous to use a laser perforation process, as opposed to electrodeposition for the manufacture of the through holes. The through holes shown in Figures 5 and 6, manufactured by laser drilling, are substantially cylindrical or tapered, in comparison with the funnel-shaped inlet and outlet of the electrodeposited through holes, for example, as disclosed in WO 01 / 18280. The vibration of the membrane, which is its speed of vibration, can be transferred to the pharmaceutical formulation over a larger area, by means of friction when the through holes are substantially cylindrical or tapered, in comparison with the entrance and exit in the form of electrodeposited through-hole funnel. The pharmaceutical formulation, because of its own inertia, is then ejected from the outlet openings of the through-holes, resulting in jets of liquid collapsing to form the aerosol. Without wishing to be bound by theory, it is believed that since an electrodeposited membrane comprises extremely folded surfaces of the through holes, the surface or area of energy transfer from the membrane to the liquid is reduced.
[000135] However, the present invention can also be implemented by electrodeposited membranes, where the nozzle portion is defined by the continuous portion of the through hole in the direction of extension from the smaller diameter of the through hole towards the first side until it reaches a diameter of 2x or 3x the smaller diameter of the orifice. In one embodiment, the total length of the through hole is measured from the smallest diameter to the first side.
[000136] Referring again to Figure 1, so that the patient does not need to remove or put the therapeutic device from his mouth after inhaling the aerosol, the mouthpiece 3 has an opening 6 sealed by an elastic valve element 7 (exhalation valve). If the patient exhales into the mouthpiece 3 and, consequently, into the nebulization chamber 2, the elastic valve element 7 opens, so that the exhaled air is able to escape from the inside of the therapeutic aerosol. By inhalation, ambient air flows through the nebulizer chamber 2. The nebulizer chamber 2 has a sealed opening (not shown) by an additional elastic valve element (inhalation valve). If the patient inhales through mouthpiece 3 and sucks from the nebulizer chamber 2, the elastic valve element opens so that the ambient air is able to enter the nebulizer chamber and is mixed with the aerosol, and allowing the nebulizer chamber 2 is inhaled. A more detailed description of this process is provided in US Patent No. 6,962,151, which is incorporated by reference in its entirety for all purposes.
[000137] The nebulizer shown in Figure 2 comprises a cylindrical storage reservoir 10 for supplying a liquid which is fed to the membrane 5. As shown in Figure 2, the oscillating membrane 5 can be arranged on an end wall 12 of the liquid reservoir cylindrical 10 to ensure that the liquid poured into the liquid reservoir comes in direct contact with the membrane 5, when the aerosol generator is held in the position shown in Figure 1. However, other methods can also be used to feed the liquid to a membrane, without any oscillating change being necessary in the design of the device according to the invention, to generate a negative pressure in the liquid reservoir.
[000138] On the side facing the end wall 12, the cylindrical liquid container 10 is opened. The opening is used to pour liquid into the liquid reservoir 10. Slightly below the opening on the outer surface 13 of the peripheral wall 14 there is a projection 15 that serves as a support when the liquid container is inserted into an opening suitably incorporated in a accommodation 35.
[000139] The open end of the liquid container 10 is closed by a flexible sealing element 16. The sealing element 16 rests on the end of the peripheral wall 14 of the liquid container 10 and extends in a pot-shaped manner. into the interior of the liquid container 10, whereby a conical wall section 17 is formed in the sealing element 16 and closed by a flat wall section 18 of the sealing element 16. As discussed further below, the forces act through the section flat wall 18 over the sealing element 16 and thus in one embodiment the flat wall section 18 is thicker than the other sections of the sealing element 16. At the perimeter of the flat wall section 18, there is a distance to the tapered wall 17, so that the tapered wall section 17 can be folded, when the flat wall section 18 is moved upstream, in relation to the representation in Figure 2.
[000140] On the side of the flat wall section 18, facing outwards from the inside of the liquid container, there is a projection comprising a truncated cone section 19 and a cylindrical section 20. This design allows the projection to be introduced and closed within an opening adapted to match the cylindrical section, since the flexible material of the sealing element 16 allows the deformation of the truncated cone section 19.
[000141] In one embodiment, the aerosol generator 4 comprises a sliding sleeve 21 equipped with an opening of this type, which is substantially a hollow cylinder opened on one side. The opening for fixing the sealing element 16 is incorporated in an end wall of the sliding sleeve 21. When the truncated cone 19 is locked in place, the end wall of the sliding sleeve 21 containing the opening rests in the wall section of the element flat sealing 18. Locking the truncated cone 19 inside the sliding sleeve allows forces to be transmitted from the sliding sleeve to the flat wall section 21 of the sealing element 16, so that the sealing section 18 follows the movements of the slide 21 slide in the direction of the longitudinal central axis of the liquid container 10.
[000142] In a generalized form, the sliding sleeve 21 can be seen as a sliding element, which can, for example, also be implemented as a sliding rod that can be attached or inserted into a drilling hole. Characteristic of the sliding element 21 is the fact that it can be used to apply a substantially linear force directed to the flat wall element 18 of the sealing element 16. In general, the decisive factor for the mode of operation of the aerosol generator according to the invention is the fact that a sliding element transmits a linear movement to the sealing element, so that an increase in volume occurs within the liquid reservoir 10. Since the liquid reservoir 10 is otherwise gas-tight, this causes the generation of negative pressure in the liquid reservoir 10.
[000143] The sealing element 16 and the sliding element 21 can be produced in a single piece, that is, in a single operation, but from different materials. The production technology for this is available, so that a one-piece component for the nebulizer is created, for example, in a fully automatic production step.
[000144] In one embodiment, the sliding sleeve 21 is opened at the end facing the drilling hole for the truncated cone, but at least two diametrically opposed protrusions 22 and 23 protruding radially into the sliding sleeve 21. A ring 24 surrounding the sliding sleeve extends radially outwards. While the rim 24 is used as a support for the slide 21 in the position shown in Figure 5, the projections 22 and 23 protruding into the slide 21 are used to absorb the forces acting on the slide 21 in particular parallel to the central longitudinal axis. In one embodiment, these forces are generated by means of two spiral grooves 25 that are located outside the peripheral wall of a rotating sleeve 26.
[000145] In one embodiment, the nebulizer can be implemented with one of the projections 22 or 23 and a groove 25. In another embodiment, an arrangement evenly distributed over two or more projections and a corresponding number of grooves is provided.
[000146] In one embodiment, the rotating sleeve 26 is also an open cylinder on one side through which the open end is arranged on the slide sleeve 21, therefore, it faces the truncated cone 19, allowing the truncated cone 19 to penetrate the rotating sleeve 26. In addition, the rotating sleeve 26 is arranged on the sliding sleeve 21 in such a way that the projections 22 and 23 are in the spiral grooves 25. The inclination of the spiral groove 25 is designed so that when the rotating sleeve 26 is rotated relative to the sliding sleeve 21, the projections 22 and 23 slide along the spiral grooves 25 causing a force directed parallel to the central longitudinal axis, to be exerted on the sliding projections 22 and 23 and, therefore, on the sliding sleeve 21. This force moves the sliding sleeve 21 in the direction of the central longitudinal axis, so that the sealing element 16, which is stuck in the drilling hole of the sliding sleeve through the cone truncates also be moved substantially parallel to the central longitudinal axis.
[000147] The displacement of the sealing element 16 in the direction of the central longitudinal axis of the liquid container 10 generates a negative pressure in the liquid container 10, determined inter alia by the distance by which the slide sleeve 21 is displaced in the direction of the central longitudinal axis . The displacement causes the initial volume VRI of the gas-tight liquid container 10 to increase to the volume VRN so that a negative pressure is generated. The displacement is in turn determined by the design of the spiral slots 25 in the rotating sleeve 26. In this way, the aerosol generator according to the invention ensures that the negative pressure in the liquid reservoir 10 can be generated in the relevant areas by means of simple structural measures.
[000148] To ensure that the forces to be applied to generate negative pressure when handling the device remain low, the rotating sleeve 26 is realized in a piece with a handle 27, the size of which is selected to allow the user to turn the handle 27, and therefore the rotating sleeve 26 manually, without much effort. The handle 27 is substantially in the form of a flattened cylinder or a truncated cone that is opened on one side, so that a peripheral grip zone 28 is formed on the outer periphery of the handle 27, which is touched by the user's hand when turning the handle. handle 27.
[000149] Due to the design of the spiral grooves 25 and the comparatively short total distance to be covered by the slide sleeve 21, in the longitudinal direction, to generate a sufficient negative pressure, in one mode, it is enough to rotate the handle 27 and, consequently, the rotating sleeve 26 through a relatively small angle of rotation. In one embodiment, the angle of rotation is within a range of 45- 360 degrees. This modality allows for easy handling of the device according to the invention and of the therapeutic aerosol generator equipped with it.
[000150] In order to create a unit that can be operated simply and uniformly from the slide sleeve 21 and the rotating sleeve 26, including the handle 27, in one embodiment, the aerosol generator described in this document has a support sleeve 29 supporting the sliding sleeve 21, which substantially comprises a smooth cylinder opened on one side. The diameter of the peripheral wall 30 of the support sleeve 29 is smaller than the internal diameter of the handle 27 and, in the example of a described embodiment, is aligned with the internal diameter of a cylindrical locking ring 31, which is supplied concentricly to the grip area 28 of the handle 27, but with a smaller diameter on the side of the handle 27, in which the rotating sleeve 26 is also arranged. Contained on the side of the cylindrical locking ring 31, facing the rotating sleeve is a peripheral locking edge 32 that can be engaged with locking lugs 33, located at intervals on the peripheral wall 30 of the support sleeve 29. This allows the handle 27 is located on the support sleeve 29 whereby, as shown in Figure 5, the handle 27 is placed on the open end of the support sleeve 29 and the locking edge 32 is interlocked with the locking lugs 33.
[000151] In order to secure the slide sleeve 21, an opening is provided in the center of the sealed end of the support sleeve 29 in which the slide sleeve 21 is arranged, as can be identified in Figure 2. The rim 24 of the slide sleeve 21 it rests in the position shown in Figure 2 on the surface of the end wall of the support sleeve 29 facing the handle. Extending into the opening of the bearing are two diametrically opposed projections 51 and 52, which project in two longitudinal grooves 53 and 54 on the peripheral surface of the slide 21. The longitudinal grooves 53 and 54 run parallel to the longitudinal axis of the slide 21 . Guide projections 51 and 52 and longitudinal grooves 53 and 54 provide anti-rotation lock for the sliding sleeve 21, so that the rotation movement of the rotating sleeve 26 does not result in rotation, but in the linear displacement of the sliding sleeve 21. As it is evident from Figure 2, this ensures that the slide sleeve 21 is maintained in combination with the handle 27 and the support sleeve 29 in an axially displaceable manner, but locked against rotation. If the handle 27 is rotated in relation to the support sleeve 29, the rotating sleeve 26 also rotates in relation to the sliding sleeve 21, so that the projections 22 and 23 move along the spiral slots 25. This causes the sleeve 21 slide is moved in an axial direction at the opening of the support sleeve 29.
[000152] It is possible to dispense with the guide projections 51 and 52 in the support opening and the longitudinal grooves 53 and 54 in the slide sleeve 21. In one embodiment, the guide projections 51 and 52 and the longitudinal grooves 53 and 54 are not present in the aerosol generator, and the cone trunk 19, the cylinder sections 20 of the sealing elements 16 and the large area support for the sliding sleeve 21 securing the truncated cone in the flat sealing element section 18 obtain anti-rotation lock of the sleeve sliding 21 by means of friction. In another embodiment, the sealing element 16 is fixed so that it is unable to rotate with respect to the support sleeve 29.
[000153] In one embodiment, a first annular sealing edge 34 concentric with the opening holding the sliding sleeve is provided on the surface of the sealed end of the support sleeve 19. The diameter of the first sealing edge 34 corresponds to the diameter of the peripheral wall 14 of the liquid container 10. As provided in Figure 2, this ensures that the first sealing edge 34 presses the sealing element 16 at the end of the peripheral wall against the liquid reservoir 10, such that liquid reservoir 10 is sealed. In addition, the first sealing edge 34 can also secure the sealing element 16, so that it is unable to rotate in relation to the liquid reservoir 10 and the support sleeve 29. In one embodiment, excessive force does not need to be applied, in order to ensure that said device components are not able to rotate in relation to each other.
[000154] In one embodiment, the necessary forces are generated, at least to a certain extent, through an interaction between handle 27 and housing 35 in which the pharmaceutical formulation reservoir is incorporated as a single piece or in which the reservoir of pharmaceutical formulation 10 (liquid) is inserted as shown in Figure 2. In this case, the reservoir of pharmaceutical formulation 10 inserted in the housing with the peripheral projection 15 rests at intervals on a support 36 in the housing 35 that extends radially into the interior of the housing 35. This allows the liquid reservoir 10 to be easily removed from compartment 35 for cleaning purposes. In the embodiment shown in Figure 2, the support is provided only at intervals, and therefore the openings are provided for ambient air, when the patient inhales, which is described in more detail below.
[000155] Figure 2 identifies a rotary lock, which is implemented by means of the handle 27 on the one hand and the housing 35, on the other. Locking projections 62 and 63 are shown in housing 35. However, there are no special requirements with regard to the design of the rotary lock, as far as the device according to the invention refers to the generation of negative pressure in the liquid reservoir. 10.
[000156] In one embodiment, the liquid reservoir 10 is configured to have a VRN volume of at least 16 ml, at least about 16 ml, at least 18 ml, at least about 18 ml, at least 20 ml or at least about 20 ml, so that when, for example, an 8 ml quantity of liquid (eg aminoglycoside pharmaceutical formulation) to be emitted in the form of an aerosol is contained (filled or poured) in) in liquid reservoir 10, an 8 ml or about 8 ml air cushion is provided. That is, the ratio between the volume VRN to the initial volume of the liquid VL within the liquid reservoir 10 is at least 2.0 and the ratio between the volume VA of a gas and VL of the liquid is at least 1.0. It has been shown that a liquid reservoir having a VRN volume of about 15.5 ml, about 19.5 ml and about 22.5 ml is sufficient and that the efficiency increases with increasing VRN.
[000157] In one embodiment, the ratio between VRN and VL is at least 2.0, at least approximately 2.0, at least 2.4, at least approximately 2.4, at least 2.8 or at least approximately 2.8. In one embodiment, the VA to VL ratio is at least 1.0, at least 1.2, at least 1.4, at least 1.6 or at least 1.8. In another embodiment, the VA to VL ratio is at least about 1.0, at least about 1.2, at least about 1.4, at least about 1.6, or at least about 1 , 8.
[000158] The volume of the air cushion, in one embodiment, is at least 2 ml, at least about 2 ml, at least 4 ml, at least about 4 ml, is at least 6 ml, at least about 6 ml, at least 8 ml, at least about 8 ml, at least 10 ml, at least about 10 ml, at least 11 ml, at least about 11 ml, at least at least 12 ml, at least about 12 ml, at least 13 ml, at least about 13 ml, at least 14 ml, or at least about 14 ml. In one embodiment, the volume of the airbag is at least about 11 ml or at least about 14 ml. In one embodiment, the volume of the air cushion is from about 6 ml to about 15 ml, and the ratio between VRN and VL is at least about 2.0 to at least about 3.0. In another embodiment, the ratio between VRN and VL is at least 2.0 to at least about 2.8.
[000159] The volume of the air cushion, in one embodiment, is about 2 ml, about 4 ml, about 6 ml, about 8 ml, about 10 ml, about 11 ml, about 12 ml , about 13 ml or about 14 ml.
[000160] In one embodiment, the ratio between the volume of VRN to the initial volume of liquid VL is at least 2.0. Theoretically, an unlimited expansion of the increase in the VRN volume of the liquid reservoir 10 will result in an almost stable negative pressure range. In one modality, the ratio between the volume VRN to the initial volume of liquid VL is within the range between 2.0 and 4.0 and in another modality it is between 2.4 and 3.2. Two examples of the different ratio ranges (VRN / VL) for different initial volume of the VL liquid between 4 ml and 8 ml are shown in Table 4, below.

[000161] The systems provided in this document can be used to treat a variety of lung infections in individuals in need of them. Among the lung infections (such as in patients with cystic fibrosis) that can be treated with the methods of the invention are Gram-negative infections. In one embodiment, the infections caused by the following bacteria are treatable with the systems and formulations provided in this document: Pseudomonasf for example, P. aeruginosa, P. paucimobilis, P. putida, P. fluorescens, and P. acidovorans), Burkholderia (for example, B. pseudomallei, B. cepacia, B. cepacia complex, B. dolosa, B. fungorum, B. gladioli, B. multivorans, B. vietnamiensis, B. pseudomallei, B. ambifaria, B. andropogonis, B anthina, B. brasilensis, B. caledonica, B. caribensis, B. caryophylli), Staphylococcus (for example, S. aureus, S. auricularis, S. carnosus, S. epidermidis, S. lugdunensis), Staphylococcus aureus resistant to methicillin (MRSA), Streptococcus (e.g., Streptococcus pneumoniae), Escherichia coli, Klebsiella, Enterobacter, Serratia, Haemophilus, Yersinia pestis, Mycobacterium, non-tuberculous mycobacteria (for example, M. avium, M. avium subsp. hominuis) , M. abscessus, M. chelonae, M. bolletii, M. kansasii, M. ulcerans, M. avium, M. avium (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 chelonae)).
[000162] In one embodiment, the systems described in this document are used to treat an infection caused by a non-tuberculous mycobacteria. In one embodiment, the systems described in this document are used to treat an infection caused by Pseudomonas aeruginosa, Mycobacterium abscessus, Mycobacterium avium or M. avium complex. In another embodiment, a patient with cystic fibrosis is treated for Pseudomonas aeruginosa, Mycobacterium abscessus, Mycobacterium avium, or Mycobacterium avium complex with one or more of the systems described in this document. In yet another modality, infection by Mycobacterium avium is Mycobacterium avium subsp. hominissuis.
[000163] In one embodiment, a patient with cystic fibrosis is treated for pulmonary infection with one of the systems provided in this document. In another embodiment, lung infection is an infection by Pseudomonas. In yet another modality, infection by Pseudomonas aeruginosa. In another modality, the aminoglycoside in the system is amikacin.
[000164] In one embodiment, the system provided in this document is used for the treatment or prophylaxis of pulmonary infection by Pseudomonas aeruginosa, Mycobacterium abscessus, Mycobacterium avium or Mycobacterium avium complex in a patient with cystic fibrosis or a patient without cystic fibrosis. In another embodiment, the system provided in this document comprises a formulation of liposomal aminoglycoside. In another embodiment, aminoglycoside is selected from amikacin, apramycin, arbecacin, astromycin, capreomycin, dibecacin, framicetin, gentamicin, hygromycin B, isepamycin, kanamycin, neomycin, netilmycin, paromomycin, rodestreptomycin, ribostamycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin, streptomycin. verdamycin or a combination thereof. In yet another embodiment, the aminoglycoside is amikacin, for example, amikacin sulfate.
[000165] An obstacle to the treatment of infectious diseases, such as Pseudomonas aeruginosa, the main cause of chronic disease in patients with cystic fibrosis is the penetration of the drug in the sputum / biofilm barrier in the epithelial cells (Figure 7). In Figure 7, the thread forms represent aminoglycoside complexed to the liposome, the symbol "+" represents free aminoglycoside, the symbol "mucin, alginate and DNA and the solid bar symbol represents Pseudomonas aeruginosa. This barrier comprises both P. aeruginosacolonizada and planktonic incorporated in alginate or exopolysaccharides from bacteria, as well as DNA from damaged leukocytes, and mucin from lung epithelial cells, all having a negative net charge.The negative charge binds and prevents the penetration of loaded drugs positively, such as aminoglycosides, rendering them biologically ineffective (Mendelman et al., 1985). Without wishing to be limited by theory, the trapping of aminoglycosides within liposomes or lipid complexes either partially or partially protects non-specific binding aminoglycosides / biofilm, allowing liposomes or lipid complexes (with aminoglycoside encaps penetrate (Figure 7).
[000166] In another embodiment, the patient is treated for pulmonary infection by non-tuberculous mycobacteria with one of the systems provided in this document. In another embodiment, the system provided herein comprises a liposomal amikacin formulation.
[000167] In another embodiment, the system provided in this document is used for the treatment or prophylaxis of one or more bacterial infections in a patient with cystic fibrosis. In another embodiment, the system comprises a formulation of liposomal aminoglycoside. In another modality, the aminoglycoside is amikacin.
[000168] In another embodiment, the system provided in this document is used for the treatment or prophylaxis of one or more bacterial infections in a patient with bronchiectasis. In another embodiment, the system provided in this document comprises a formulation of liposomal aminoglycoside. In another embodiment, the aminoglycoside is amikacin or amikacin sulfate.
[000169] In yet another modality, the system provided in this document is used for the treatment or prophylaxis of pulmonary infections by Pseudomonas aeruginosa in patients who do not have CF bronchiectasis. In another embodiment, the system provided in this document comprises a formulation of liposomal aminoglycoside. In another modality, the aminoglycoside is amikacin.
[000170] As provided herein, the present invention provides aminoglycoside formulations administered via inhalation. In one embodiment, the aerosol MMAD is about 3.2 pm to about 4.2 pm, as measured by the Andersen Cascade Impactor (ACI), or about 4.4 pm to about 4.9 pm, measured by the Next Generation Impactor (NGI).
[000171] In one embodiment, the nebulization time for an effective amount of an aminoglycoside formulation provided in this document is less than 20 minutes, less than 18 minutes, less than 16 minutes or less than 15 minutes. In one embodiment, the nebulization time for an effective amount of an aminoglycoside formulation provided herein is less than 15 minutes or less than 13 minutes. In one embodiment, the nebulization time for an effective amount of an aminoglycoside formulation provided herein is about 13 minutes.
[000172] In one embodiment, the formulation described in this document is administered once a day to a patient who needs it. EXAMPLES
[000173] The present invention is further illustrated by reference to the Examples that follow. However, it should be noted that these Examples, like the modalities described above, are illustrative and should not be construed as restricting the scope of the invention in any way. Example 1: Comparison of nebulizer reservoir volumes
[000174] In this example, the aerosol generator was a research eFlow® nebulizer, modified for use with liposomal aminoglycoside formulations supplied from Pari Pharma GmbH, Germany. A first aerosol generator had an initial VRI reservoir volume of 13 ml (A), a second of 17 ml (B), a third of 22 ml (C) and a quarter of 20 ml (D). That is, the increase in VRN volume of the first was 15.5 mL, the second 19.5 mL, the third 24.5 mL and the fourth 22.5 mL.
[000175] The 8 ml of a liposomal amikacin formulation was poured into the liquid reservoir 10. As shown in Figure 8, an 8 ml air cushion resulted in an aerosol generation time period when the complete emission of 8 mL of the formulation in the liquid reservoir between 14 and 16 minutes. A 12 mL air cushion, however, reduced the aerosol generation time to between 12 and about 13 minutes. The 17 mL airbag further decreases the aerosol generation time to between 10 and 12 minutes (Figure 6).
[000176] In addition, the first version (A) and the third version (C) of the aerosol generator had been used together with 8 ml of the liposomal amikacin formulation. An initial negative pressure of 50 mbar or less was generated inside the liquid reservoir. In addition, the negative pressure was measured during aerosol generation and is shown over the aerosol generation time in Figure 9. In other words, Figure 9 shows the experimental data comparing the negative pressure interval during the generation time. of aerosol to a liquid reservoir (C) having a VRN volume of 24.5 ml and a liquid reservoir (A) having a VRN volume of 15.5 ml. The initial value of the amikacin VL formulation was 8 ml and the initial negative pressure was about 50 mbar (5 kPa). The graph indicates that an air cushion prevents the greatest negative pressure from rising above a critical value of 300 mbar (30 kPa).
[000177] The dependence on the efficiency of the aerosol generator (proportional to the rate of liquid yield or the rate of total yield) at different negative pressures was measured with the nebulizer described above. A liposomal amikacin formulation having a viscosity in the range of 5.5-14.5 mPa.s at shear forces between 1.1 and 7.4 Pa (thixotrope) was used in the experiment. As shown in Figure 10, efficiency is optimal over a negative pressure range, between 150 mbar (15 kPa) and 300 mbar (30 kPa). Also as shown in Figure 10, efficiency decreases at a negative pressure below approximately 150 mbar (15 kPa) and at a negative pressure above 300 mbar (30 kPa).
[000178] In addition, the same liposomal amikacin formulation as in Figure 8 was used in four different aerosol generators based on the modified eFlow®, where the first aerosol generator (A) is a modified eFlow® with an increase of VRN volume of the liquid reservoir is 19.5 ml and filled with 8 ml of the liposomal formulation amikacin.
[000179] The second aerosol generator (B) had a reservoir with a larger volume VR of 16 ml filled with 8 ml of the mentioned liposomal amikacin formulation, the third aerosol generator (C) had an increased volume VRN of 24.5 ml, filled with 8 ml of mentioned liquid. The fourth aerosol generator had an increased VRN volume of the liquid reservoir of 22.5 ml and was filled with 8 ml of the above mentioned liposomal amikacin formulation.
[000180] Figure 11 shows experimental data from these four aerosol generators filled with 8 ml of the liposomal amikacin formulation. The results show the time of aerosol generation for complete emission of the liposomal amikacin formulation into the liquid reservoir in relation to the ratio between the volume increase in the liquid reservoir (VRN) to the initial volume of liquid in the liquid reservoir before of use (VL). Figure 11 indicates that with the modified aerosol generating device (A) an aerosol generation time of about 16 minutes was required, whereas the aerosol generation time decreased with an increase in the VRN / VL ratio. The data also shows that the aerosol generation time can be reduced by about 4 minutes to 12 minutes thereafter with the third aerosol generating device (C).
[000181] The data provided in Example 1, therefore, indicates that a larger airbag allows the operation of the aerosol generator for a long time in an efficient negative pressure range, so that the total aerosol generation time can significantly reduced. Therefore, even large amounts of liquid, such as 8 mL, can be nebulized (emitted as an aerosol) in less than 12 minutes. Example 2: Aerosol properties of the amikacin formulation
[000182] Eleven different batches of the liposomal amikacin formulation were examined with the modified eFlow® nebulizer (ie modified for use with the liposomal aminoglycoside formulations described in this document) which has a modified 40 mesh membrane, manufactured as described in present document, and a reservoir with a capacity of 8 mL of liquid and airbag mentioned above. Cascade impaction was performed using ACI (Andersen Cascade Impactor) or NGI (Next Generation Impactor) to establish aerosol properties: mass mean aerodynamic diameter (MMAD), geometric standard deviation (DPG) and fine particle fraction (FPF) . Measurement of the Average Aerodynamic Diameter (MMAD) with ACI
[000183] An Andersen Cascade Impactor (ACI) was used for MMAD measurements and the fogging work was carried out inside a ClimateZone chamber (Westech Instruments Inc., GA) to maintain the temperature and the relative humidity percentage during fogging. The ClimateZone has been pre-set at a temperature of 18 ° C and a relative humidity of 50%. ACI was assembled and loaded within ClimateZone. A probe thermometer (VWR dual thermometer) was attached to the ACI surface in phase 3 to monitor the ACI temperature. Nebulization was started when the ICA temperature reached 18 ± 0.5 ° C.
[000184] With the 8 mL doses loaded with 8 mL, it was found that the ICA could not handle the entire 8 mL dose; that is, the liposomal amikacin formulation deposited on ACI plate 3 overflowed. It was determined that the percentage of drug distribution at each ACI stage was not affected by the amount of liposomal formulation of amikacin collected inside the ACI, as long as there was no discharge of liquid in the ACI stage 3 (data not shown). Therefore, for nebulization, the nebulizer was filled with either 4 ml of liposomal amikacin formulation and nebulized until empty or filled with 8 ml of liposomal amikacin formulation and nebulized for about 6 minutes of collection time (ie, ~ 4 mL).
[000185] The nebulizer was collected at a flow rate of 28.3 L / min. in the ACI which was cooled to 18 ° C. The nebulization time was recorded and the nebulization rate calculated based on the weight difference (nebulized quantity) divided by the time interval.
[000186] After the nebulizer was collected, ACI collection plates 0, 1, 2, 3, 4, 5, 6 and 7 were removed, and each was loaded in its own petri dish. An appropriate amount of extraction solution (20 mL for plates 2, 3 and 4, and 10 mL for plates 0, 1, 5, 6 and 7) was added to each Petri plate to dissolve the formulation deposited on each plate. Samples of plates 0, 1, 2, 3, 4, 5 and 6 were more appropriately diluted with the mobile phase C for HPLC analysis. Sample from plate 7 was directly analyzed by HPLC without any further dilution. The ACI filter was also transferred to a 20 ml bottle and 10 ml of extraction solution, and the capped bottle was vortexed to dissolve any formulation deposited on it. The liquid samples from the flask were filtered (0.2 pm) in HPLC flasks for HPLC analysis. The induction hole with the connector was also rinsed with 10 ml of extraction solution to dissolve the formulation deposited on it, and the sample was collected and analyzed by HPLC with two-time dilution. Based on the amount of amikacin deposited in each stage of the impactor, the mass mean aerodynamic diameter (MMAD), the geometric standard deviation (GSD) and fine particle fraction (FPF) were calculated.
[000187] In the case of nebulizers loaded with 8 mL and nebulized for 6 minutes, dose of fine particles (FPD) was normalized to the volume of the nebulized formulation, in order to compare the FPD in all experiments. FPD (normalized to the volume of the nebulized formulation) was calculated according to the following equation: FPD (normalized to the nebulized volume) (mg / mL) = Amikacin Recovered x FPF (mg) Nebulized aricace (g) -s-Density (g / mL) Measurement of Aerodynamic DiameterMass Mass (MMAD) with NGI
[000188] A Next Generation Impactor (NGI) was also used for MMAD measurements and the fogging work was carried out inside a ClimateZone chamber (Westech Instruments Inc., GA) to maintain the temperature and percentage of relative humidity during fogging. ClimateZone has been pre-set for a temperature of 18 ° C and a relative humidity of 50%. The NGI was assembled and loaded into ClimateZone. A probe thermometer (VWR dual thermometer) was attached to the NGI surface to monitor the NGI temperature. Nebulization was started when the NGI temperature reached 18 ± 0.5 ° C.
[000189] 8 ml of the liposomal amikacin formulation was added to the nebulizer being nebulized. When no aerosol was observed, the timer was stopped. The nebulizer was collected at a flow rate of 15 L / min. in the NGI which was cooled to 18 ° C. The nebulization time was recorded and the nebulization rate calculated based on the weight difference (nebulized quantity) divided by the time interval.
[000190] After the aerosol collection was made, the NGI tray with tray support was removed from the NGI. A suitable amount of extraction solution was added to the NGI 1, 2, 3, 4, 5, 6, 7 and MOC cups to dissolve the formulation deposited on these cups. This material was transferred, respectively, to a volumetric flask. For NGI cups 1, 2 and 6, 25 mL volumetric flasks were used; for NGI cups 2, 3, 4, 50, 50 ml volumetric flasks were used. More extraction solution was added to the cups and again transferred to the volumetric flask. This procedure was repeated several times in order to completely transfer the formulation deposited on the NGI cup to the volumetric flask. The volumetric flasks were covered to bring the final volume to both 25 mL and 50 mL and shaken well before sampling. Samples from cups 1, 2, 3, 4, 5, 6 and 7 were further diluted with the mobile phase C for HPLC analysis. MOC sample was directly analyzed by HPLC without any further dilution. The NGI filter was also transferred to a 20 mL bottle and 10 mL of extraction solution was added, and the bottle capped and vortexed to dissolve any formulation deposited on it. The liquid samples from the flasks were filtered (0.2 pm) into HPLC flasks for HPLC analysis. The induction hole with connector was also rinsed with 10 ml of extraction solution to dissolve the formulation deposited on it, and the sample was collected and analyzed by HPLC with an 11-fold dilution.
[000191] Based on the amount of amikacin deposited in each phase of the impactor, MMAD, GSD and FPF were calculated.
[000192] FPD was normalized to the volume of the nebulized formulation in order to compare DPF in all experiments. FPD (normalized to the volume of the nebulized formulation) was calculated according to the following equation: FPD (normalized to the nebulized volume) (mg / mL) = Amikacin Recovered x FPF (mg) Nebulized Arikace (g) -s-Density (g / mL)
[000193] The results of these experiments provided in Figures 12 and 13 and Table 5 below.

Example 3: Nebulization rate study
[000194] Nebulization rate studies (grams of nebulized formulation per minute) were conducted in a biosafety cabinet (Model 1168, Type B2, FORMA Scientific). The assembled nebulizer (handle with mouthpiece and aerosol head) was first weighed empty (Wi), then a certain volume of the formulation was added and the nebulizer device was weighed again (W2). The nebulizer at a flow rate of ~ 8 L / min. (See figure 14 for details of the experiment). When the aerosol was no longer observed, the timer was stopped. The nebulizer was weighed again (W3) and the nebulization time (t) was recorded. The total nebulized formulation was calculated as W2-W3 and the total drug residue after nebulization was calculated as W3-W1. The nebulization rate was calculated according to the following equation:

[000195] Fogging rates in g / min. as well as other correlated results for nebulized liposomal amikacin using a nebulizer manufactured according to specifications (twenty-four aerosol heads were selected and used in these studies) are shown in Table 6. TABLE 6. FORMULATION FILLING RATES (G / MIN.)


Example 4: Amikacin percentage associated with nebulization and nebulization characterization
[000196] The free and liposome-complexed amikacin in the nebulizer of Example 3 was measured. As mentioned in Example 3, the nebulizer was collected in a refrigerated impact device at a flow rate of 8 L / min. (Figure 14).
[000197] The nebulizer collected in the impact device was rinsed with 1.5% NaCl and transferred to a 100 ml or 50 ml volumetric flask. The impact device was then rinsed several times with 1.5% NaCl in order to transfer all the formulation deposited in the impact device to the flask. To measure the free amikacin concentration of the nebulizer, 0.5 mL of the diluted nebulizer inside the volumetric flask was taken and loaded into an Arnicon® Ultra - 0.5 mL 30 K centrifugal filter device (regenerated cellulose, 30K MWCO, Millipore) and this device was centrifuged at 5,000 G at 15 ° C for 15 minutes. An appropriate amount of filtrate was removed and diluted 51 times with a mobile phase C solution. The concentration of amikacin was determined by HPLC. To measure the total amikacin concentration of the nebuliser, an appropriate amount of the nebulizer was diluted inside the volumetric flask and diluted (also dissolved) 101 times in extraction solution (perfluoropentanic acid: 1- propanol: water (25: 225: 250, v / v / v)) and the concentration of amikacin was determined by HPLC.
[000198] The percentage of associated amikacin after nebulization was calculated by the following equation:

[000199] The percentage of associated amikacin after nebulization and full dose recovery from nebulization experiments described in Table 6 are summarized in Table 7. Corresponding nebulization rates were also included in Table 7.



[000200] The total concentration of amikacin in the liposomal amikacin formulation was measured during this study, with the rest of the samples, using the same HPLC and amikacin standard. The value obtained was 64 mg / ml of amikacin. The values of associated percentage of amikacin after nebulization ranged from 58.1% to 72.7%, with an average value of 65.5 ± 2.6%; for 8 mL of nebulized liposomal amikacin formulation, the total amount of amikacin recovered ranged from 426 mg to 519 mg, with an average value of 47 6 ± 17 mg; the calculated amount of nebulized amikacin (according to the weight of the nebulized liposomal amikacin formulation in Table 7) ranged from 471 mg to 501 mg, with an average value of 490 ± 8 mg; the total recovery of amikacin varied from 91% to 104%, with an average value of 97 ± 3% (n = 72). Liposome Size
[000201] The liposomal amikacin formulation (64 mg / ml amikacin), whether pre-nebulized or post-nebulized, was appropriately diluted with 1.5% NaCl and the size of the liposome particles was measured by light scattering , using a Nicomp 380 Submicron Particle Sizer (Nicomp, Santa Barbara, CA).
[000202] Post-nebulization liposome sizes of the aerosolized liposomal amikacin formulation with twenty-four aerosol nebulizer heads with 8 mL reservoirs were measured. The size of the liposome varied from 248.9 nm to 288.6 nm, with an average of 264.8 ± 6.7 nm (n = 72). These results are shown in Table 8. The average pre-nebulized liposome diameter was approximately 285 nm (284.5 nm ± 6.3 nm).



[000203] All documents, patents, patent applications, publications, product descriptions, and protocols that are cited throughout this application are incorporated into this document as a reference in its entirety for all purposes.
[00204] The modalities illustrated and discussed in the specification are intended only to teach those skilled in the art the best way known by the inventors to prepare and use the invention. Modifications and variations of the modalities of the invention described above are possible without departing from the invention, as appreciated by those skilled in the art in light of the previous teachings. It is understood, therefore, that, within the scope of the claims and their equivalents, the invention can be practiced in a manner other than that specifically described.

权利要求:
Claims (26)
[0001]
1. System for the treatment or prophylaxis against pulmonary infection in a patient characterized by comprising: (a) a pharmaceutical formulation comprising an aqueous dispersion of aminoglycoside complexed to the liposome, in which the lipid component of the aminoglycoside complexed to the liposome is present in 45-60 mg / mL and consists of dipalmitoylphosphatidylcholine (DPPC) and cholesterol; and (b) a nebulizer comprising a vibrating mesh membrane that generates an aerosol of the pharmaceutical formulation at a rate of 0.60 g / min to 0.80 g / min, the fine particle fraction (FPF) of the aerosol is greater or equal to 64%, as measured by the Andersen Cascade Impactor (ACI), or greater than or equal to 51%, as measured by the Next Generation Impactor (NGI), and the percentage associated with aminoglycoside post-nebulization is 60% to 70% .
[0002]
2. System according to claim 1, characterized by the fact that the aminoglycoside is selected from amikacin, apramycin, arbecacin, astromycin, capreomycin, dibecacin, framicetin, gentamycin, hygromycin B, isepamycin, kanamycin, neomycin, netilmycin, paromycin, rodomycin, rodomycin , ribostamycin, sisomycin, spectinomycin, streptomycin, tobramycin, verdamycin or a combination thereof.
[0003]
3. System according to claim 1 or 2, characterized by the fact that the aminoglycoside is amikacin.
[0004]
A system according to any one of claims 1 to 3, characterized by the fact that the aminoglycoside is amikacin sulfate.
[0005]
System according to any one of claims 1 to 4, characterized by the fact that the liposomes of the aminoglycoside complexed to the liposome are unilamellar vesicles, multilamellar vesicles or a mixture thereof.
[0006]
6. System according to any one of claims 1 to 5, characterized by the fact that the aminoglycoside is amikacin, and the liposomes of the aminoglycoside complexed to the liposome are unilamellar vesicles, multilamellar vesicles or a mixture thereof.
[0007]
7. System according to any one of claims 1 to 6, characterized by the fact that the fraction of fine particles (FPF) of the aerosolized pharmaceutical formulation is 64% to 80%, as measured by ACI; or from 51% to 65%, as measured by NGI.
[0008]
8. Use of a pharmaceutical formulation, as defined in claim 1, characterized by being in the preparation of a medication for the treatment or prophylaxis of a lung infection in a patient, in which the medication is an aerosol, and the aerosol is generated by aerosolization of the pharmaceutical formulation via a nebulizer comprising a vibrating mesh membrane at a rate of 0.60 g / min to 0.80 g / min, the fine particle fraction (FPF) of the aerosol is greater than or equal to 64%, as measured by Andersen Cascade Impactor (ACI), or greater than or equal to 51%, as measured by Next Generation Impactor (NGI), and the percentage associated with aminoglycoside post-nebulization is 60% to 70%.
[0009]
9. Use according to claim 8, characterized by the fact that the aminoglycoside is amikacin, apramycin, arbecacin, astromycin, capreomycin, dibecacin, framicetin, gentamicin, hygromycin B, isepamycin, kanamycin, neomycin, netilmycin, paromomycin, ribostamycin, sisomycin, rodestreptomycin, spectinomycin, streptomycin, tobramycin, verdamycin or a combination thereof.
[0010]
10. Use according to claim 8, characterized by the fact that the aminoglycoside is amikacin.
[0011]
11. Use according to claim 10, characterized by the fact that amikacin is amikacin sulfate.
[0012]
12. Use, according to claim 8, characterized by the fact that lung infection is an infection by non-tuberculous mycobacteria.
[0013]
13. Use, according to claim 8, characterized by the fact that the fraction of fine particles (FPF) of the aerosolized pharmaceutical formulation is 64% to 80%, as measured by ACI; or from 51% to 65%, as measured by NGI.
[0014]
14. Use according to claim 12, characterized by the fact that infection with non-tuberculous mycobacteria is an infection with M. avium, M. aviumsubsp. hominissuis (MAH), M. abscessus, M. chelonae, M. bolletii, M. kansasii, M. ulcerans, M. avium (MAC) complex (M. avium and M. intracellulare), M. conspicuum, M. kansasii, M. peregrinum, M. immunogenum, M. xenopi, M. marinum, M. malmoense, M. mucogenicum, M. nonchromogenicum, M. scrofulaceum, M. simiae, M. smegmatis, M. szulgai, M. terrae, M complex terrae, M. haemophilum, M. genavense, M. asiaticum, M. shimoidei, M. gordonae, M. nonchromogenicum, M. triplex, M. lentiflavum, M. celatum, M. fortuitum or M. fortuitum complex (M. fortuitum and chelonae).
[0015]
15. Use, according to claim 14, characterized by the fact that infection with non-tuberculous mycobacteria is an infection with the M. avium complex (MAC).
[0016]
16. Use according to claim 15, characterized by the fact that the amino glycoside is amikacin.
[0017]
17. Use according to claim 16, characterized by the fact that amikacin is amikacin sulfate.
[0018]
18. Use, according to claim 8, characterized by the fact that pulmonary infection is an infection by non-tuberculous mycobacteria and the aminoglycoside is amikacin sulfate.
[0019]
19. Use, according to claim 8, characterized by the fact that pulmonary infection is an infection of the M. avium complex (MAC) and the aminoglycoside is amikacin sulfate.
[0020]
20. System according to claim 1, characterized by the fact that the mass mean aerodynamic diameter (MMAD) of the aerosol is less than 4.2 pm, as measured by ACI, or less than 4.9 pm, as measured by NGI.
[0021]
21. System, according to claim 20, characterized by the fact that the aerosol MMAD is from 3.2 pm to 4.2 pm, as measured by the ACI; or from 4.4 pm to 4.9 pm, as measured by the NGI.
[0022]
22. Use according to claim 8, characterized by the fact that the mass mean aerodynamic diameter (MMAD) of the aerosol is less than 4.2 -pm, as measured by the ACI, or less than 4.9 pm, as measured by the NGI.
[0023]
23. Use, according to claim 22, characterized by the fact that the MMAD of the aerosol is from 3.2 pm to 4.2 pm, as measured by the ACI; or from 4.4 pm to 4.9 pm, as measured by the NGI.
[0024]
24. System according to any one of claims 1 to 7, 20 and 21, characterized by the fact that lung infection is an infection by non-tuberculous mycobacteria.
[0025]
25. System according to claim 24, characterized by the fact that infection with non-tuberculous mycobacteria is an infection with M. avium, M. aviumsubsp. hominissuis (MAH), M. abscessus, M. chelonae, M. bolletii, M. kansasii, M. ulcerans, M. avium (MAC) complex (M. avium and M. intracellulare), M. conspicuum, M. kansasii, M. peregrinum, M. immunogenum, M. xenopi, M. marinum, M. malmoense, M. mucogenicum, M. nonchromogenicum, M. scrofulaceum, M. simiae, M. smegmatis, M. szulgai, M. terrae, M complex terrae, M. haemophilum, M. genavense, M. asiaticum, M. shimoidei, M. gordonae, M. nonchromogenicum, M. triplex, M. lentiflavum, M. celatum, M. fortuitum or M. fortuitum complex (M. fortuitum and chelonae).
[0026]
26. System according to claim 24 or 25, characterized by the fact that infection with non-tuberculous mycobacteria is an infection with the M. avium complex (MAC).

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-03-06| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-03-13| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-03-20| B06I| Publication of requirement cancelled [chapter 6.9 patent gazette]|Free format text: ANULADA A PUBLICACAO CODIGO 6.6.1 NA RPI NO 2462 DE 13/03/2018 POR TER SIDO INDEVIDA. |

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2019-04-16| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-07-02| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|

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2020-02-04| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

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2020-06-30| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-11-17| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 21/05/2013, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201261649830P| true| 2012-05-21|2012-05-21|

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US61/649,830|2012-05-21|

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PCT/US2013/042113|WO2013177226A1|2012-05-21|2013-05-21|Systems for treating pulmonary infections|

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