US20150272880A1 - Systems for treating pulmonary infections - Google Patents

Systems for treating pulmonary infections Download PDF

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US20150272880A1
US20150272880A1 US14/430,179 US201314430179A US2015272880A1 US 20150272880 A1 US20150272880 A1 US 20150272880A1 US 201314430179 A US201314430179 A US 201314430179A US 2015272880 A1 US2015272880 A1 US 2015272880A1
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aminoglycoside
amikacin
aerosol
formulation
pharmaceutical formulation
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Inventor
Dominique Seidel
Philipp Holzmann
Harald Schulz
Michael Hahn
Walter Perkins
Vladimir Malinin
Xingong Li
Brian Miller
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PARI Pharma GmbH
Insmed Inc
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PARI Pharma GmbH
Insmed Inc
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Assigned to INSMED INCORPORATED reassignment INSMED INCORPORATED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LI, XINGONG, MILLER, BRIAN, MALININ, VLADIMIR, PERKINS, WALTER
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    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
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    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
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    • A—HUMAN NECESSITIES
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    • A61M2207/00—Methods of manufacture, assembly or production

Definitions

  • Certain technologies suitable for administration by inhalation employ liposomes and lipid complexes supply a prolonged therapeutic effect of drug in the lung. These technologies also provide the drug with sustained activities, and the ability to target and enhance the uptake of the drug into sites of disease.
  • Cystic fibrosis (CF) patients have thick mucus and/or sputum secretions in the lungs, frequent consequential infections, and biofilms resulting from bacterial colonizations. All these fluids and materials create barriers to effectively targeting infections with aminoglycosides. Liposomal aminoglycoside formulations may be useful in combating the bacterial biofilms.
  • the present invention provides methods for treating various pulmonary infections, including mycobacterial infections (e.g., pulmonary infections caused by nontuberculous mycobacterium, also referred to herein as nontuberculous mycobacterial (NTM) infections), by providing systems for delivery of aerosolized liposomal formulations via inhalation.
  • mycobacterial infections e.g., pulmonary infections caused by nontuberculous mycobacterium, also referred to herein as nontuberculous mycobacterial (NTM) infections
  • NTM nontuberculous mycobacterial
  • the systems and methods provided herein can be used to treat a pulmonary nontuberculous mycobacterial infection such as pulmonary M. avium, M avium subsp. hominissuis (MAH), M. abscessus, M chelonae, M. bolletii, M. kansasii, M ulcerans, M avium, M avium complex (MAC) ( M.
  • 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 M. fortuitum complex ( M. fortuitum and M. chelonae ) infection.
  • the present invention provides a system for treating or providing prophylaxis against a pulmonary infection.
  • the system comprises a pharmaceutical formulation comprising a liposomal complexed aminoglycoside, wherein the formulation is a dispersion (e.g., a liposomal solution or suspension), the lipid component of the liposome consists of electrically neutral lipids, and a nebulizer which generates an aerosol of the pharmaceutical formulation at a rate greater than about 0.53 g per minute.
  • the mass median aerodynamic diameter (MMAD) of the aerosol is less than about 4.2 ⁇ m, as measured by the Anderson Cascade Impactor (ACI), about 3.2 ⁇ m to about 4.2 ⁇ m, as measured by the ACI, or less than about 4.9 ⁇ m, as measured by the Next Generation Impactor (NGI), or about 4.4 ⁇ m to about 4.9 ⁇ m, as measured by the NGI.
  • ACI Anderson Cascade Impactor
  • NGI Next Generation Impactor
  • the system for treating or providing prophylaxis against a pulmonary infection comprises a pharmaceutical formulation comprising a liposomal complexed aminoglycoside, wherein the formulation is a dispersion (e.g., a liposomal solution or suspension), the lipid component of the liposome consists of electrically neutral lipids, and a nebulizer which generates an aerosol of the pharmaceutical formulation at a rate greater than about 0.53 g per minute.
  • the fine particle fraction (FPF) of the aerosol is greater than or equal to about 64%, as measured by the Anderson Cascade Impactor (ACI), or greater than or equal to about 51%, as measured by the Next Generation Impactor (NGI).
  • the system provided herein comprises a pharmaceutical formulation comprising an aminoglycoside.
  • the aminoglycoside is amikacin, apramycin, arbekacin, astromicin, capreomycin, dibekacin, framycetin, gentamicin, hygromycin B, isepamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodestreptomycin, ribostamycin, sisomicin, spectinomycin, streptomycin, tobramycin, verdamicin or a combination thereof.
  • the aminoglycoside is amikacin.
  • the aminoglycoside is selected from an aminoglycoside set forth in Table A, below, or a combination thereof.
  • the pharmaceutical formulations provided herein are dispersions of liposomes (i.e., liposomal dispersions or aqueous liposomal dispersions which can be either liposomal solutions or liposomal suspensions).
  • the lipid component of the liposomes consists essentially of one or more electrically neutral lipids.
  • the electrically neutral lipid comprises a phospholipid and a sterol.
  • the phospholipid is dipalmitoylphosphatidylcholine (DPPC) and the sterol is cholesterol.
  • DPPC dipalmitoylphosphatidylcholine
  • the lipid to drug ratio in the aminoglycoside pharmaceutical formulation is about 2:1, about 2:1 or less, about 1:1, about 1:1 or less, or about 0.7:1.
  • the aerosolized aminoglycoside formulation upon nebulization, has an aerosol droplet size of about 1 ⁇ m to about 3.8 ⁇ m, about 1.0 ⁇ m to 4.8 ⁇ m, about 3.8 ⁇ am to about 4.8 ⁇ m, or about 4.0 ⁇ m to about 4.5 ⁇ m.
  • the aminoglycoside is amikacin.
  • the amikacin is amikacin sulfate.
  • about 70% to about 100% of the aminoglycoside present in the formulation is liposomal complexed, e.g., encapsulated in a plurality of liposomes, prior to nebulization.
  • the aminoglycoside is selected from an aminoglycoside provided in Table A.
  • the aminoglycoside is an amikacin.
  • about 80% to about 100% of the amikacin is liposomal complexed, or about 80% to about 100% of the amikacin is encapsulated in a plurality of liposomes.
  • 80% to about 100%, about 80% to about 99%, about 90% to about 100%, 90% to about 99%, or about 95% to about 99% of the aminoglycoside present in the formulation is liposomal complexed prior to nebulization.
  • the percent liposomal complexed (also referred to herein as “liposomal associated”) aminoglycoside post-nebulization is from 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%.
  • the aminoglycoside is selected from an aminoglycoside provided in Table A.
  • the aminoglycoside is amikacin.
  • the amikacin is amikacin sulfate.
  • the present invention provides methods for treating or providing prophylaxis against a pulmonary infection.
  • the pulmonary infection is a pulmonary infection caused by a gram negative bacterium (also referred to herein as a gram negative bacterial infection).
  • the pulmonary infection is a Pseudomonas infection, e.g., a Pseudomonas aeruginosa infection.
  • the pulmonary infection is caused by one of the Pseudomonas species provided in Table B, below.
  • a patient is treated for mycobacterial lung infection with one of the systems provided herein.
  • the mycobacterial pulmonary infection is a nontuberculous mycobacterial pulmonary infection, a Mycobacterium abscessus pulmonary infection or a Mycobacterium avium complex pulmonary infection.
  • the patient is a cystic fibrosis patient.
  • a patient with cystic fibrosis is treated for a pulmonary infection with one of the systems provided herein.
  • the pulmonary infection is caused by Mycobacterium abscessus, Mycobacterium avium complex, or P. aeruginosa .
  • the pulmonary infection is caused by a nontuberculous 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. intracellulare ), M.
  • a method for treating or providing prophylaxis against a pulmonary infection in a patient comprises aerosolizing a pharmaceutical formulation comprising a liposomal complexed aminoglycoside, wherein the pharmaceutical formulation is an aqueous dispersion of liposomes (e.g., a liposomal solution or liposomal suspension), and is aerosolized at a rate greater than about 0.53 gram per minute.
  • the method further comprises administering the aerosolized pharmaceutical formulation to the lungs of the patient; wherein the aerosolized pharmaceutical formulation comprises a mixture of free aminoglycoside and liposomal complexed aminoglycoside, and the lipid component of the liposome consists of electrically neutral lipids.
  • the mass median aerodynamic diameter (MMAD) of the aerosol is about 1.0 ⁇ m to about 4.2 ⁇ m as measured by the ACI. In any one of the proceeding embodiments, the MMAD of the aerosol is about 3.2 ⁇ m to about 4.2 ⁇ m as measured by the ACI. In any one of the proceeding embodiments, the MMAD of the aerosol is about 1.0 ⁇ m to about 4.9 ⁇ m as measured by the NGI. In any one of the proceeding embodiments, the MMAD of the aerosol is about 4.4 ⁇ m to about 4.9 ⁇ m as measured by the NGI.
  • the method comprises aerosolizing a pharmaceutical formulation comprising a liposomal complexed aminoglycoside, wherein the pharmaceutical formulation is an aqueous dispersion and is aerosolized at a rate greater than about 0.53 gram per minute.
  • the method further comprises administering the aerosolized pharmaceutical formulation to the lungs of the patient; wherein the aerosolized pharmaceutical formulation comprises a mixture of free aminoglycoside and liposomal complexed aminoglycoside (e.g., aminoglycoside encapsulated in a liposome), and the liposome component of the formulation consists of electrically neutral lipids.
  • fine particle fraction (FPF) of the aerosol is greater than or equal to about 64%, as measured by the ACI, or greater than or equal to about 51%, as measured by the NGI.
  • a liposomal complexed aminoglycoside aerosol (e.g., a liposomal complexed aminoglycoside) is provided.
  • the aerosol comprises an aminoglycoside and a plurality of liposomes comprising DPPC and cholesterol, wherein about 65% to about 75% of the aminoglycoside is liposomal complexed and the aerosol is generated at a rate greater than about 0.53 gram per minute.
  • about 65% to about 75% of the aminoglycoside is liposomal complexed, and the aerosol is generated at a rate greater than about 0.53 gram per minute.
  • the aerosol is generated at a rate greater than about 0.54 gram per minute. In any one of the proceeding embodiments, the aerosol is generated at a rate greater than about 0.55 gram per minute.
  • the aminoglycoside is selected from an aminoglycoside provided in Table A.
  • the MMAD of the liposomal complexed aminoglycoside aerosol is about 3.2 ⁇ m to about 4.2 ⁇ am, as measured by the ACI, or about 4.4 ⁇ m to about 4.9 ⁇ m, as measured by the NGI.
  • the aerosol comprises an aminoglycoside and a plurality of liposomes comprising DPPC and cholesterol, wherein about 65% to about 75% of the aminoglycoside is liposomal complexed (e.g., encapsulated in the plurality of the liposomes), and the liposomal aminoglycoside aerosol is generated at a rate greater than about 0.53 gram per minute.
  • the aminoglycoside is selected from an aminoglycoside provided in Table A.
  • the FPF of the lipid-complexed aminoglycoside aerosol is greater than or equal to about 64%, as measured by the Anderson Cascade Impactor (ACI), or greater than or equal to about 51%, as measured by the Next Generation Impactor (NGI).
  • the aerosol comprises an aminoglycoside and a plurality of liposomes comprising DPPC and cholesterol, wherein about 65% to about 75% of the aminoglycoside is liposomal complexed, for example, encapsulated in the plurality of the liposomes, and the liposomal aminoglycoside aerosol is generated at a rate greater than about 0.53 gram per minute.
  • the aerosol is generated at a rate greater than about 0.54 gram per minute. In any one of the proceeding embodiments, the aerosol is generated at a rate or greater than about 0.55 gram per minute.
  • the aminoglycoside is selected from an aminoglycoside provided in Table A.
  • the aerosol comprises an aminoglycoside and a plurality of liposomes comprising DPPC and cholesterol, wherein about 65% to about 75% of the aminoglycoside is liposomal complexed. In a further embodiment, about 65% to about 75% of the aminoglycoside is encapsulated in the plurality of liposomes. In a further embodiment, the aerosol is generated at a rate greater than about 0.53 gram per minute, greater than about 0.54 gram per minute, or greater than about 0.55 gram per minute. In a further embodiment, the aminoglycoside is amikacin (e.g., amikacin sulfate).
  • amikacin e.g., amikacin sulfate
  • the concentration of the aminoglycoside in the liposomal complexed aminoglycoside is about 50 mg/mL or greater. In a further embodiment, the concentration of the aminoglycoside in the liposomal complexed aminoglycoside is about 60 mg/mL or greater. In a further embodiment, the concentration of the aminoglycoside in the liposomal complexed aminoglycoside is about 70 mg/mL or greater, for example about 70 mg/mL to about 75 mg/mL. In a further embodiment, the aminoglycoside is selected from an aminoglycoside provided in Table A. In even a further embodiment, the aminoglycoside is amikacin (e.g., amikacin sulfate).
  • amikacin e.g., amikacin sulfate
  • FIG. 1 shows a diagram of a nebulizer (aerosol generator) in which the present invention may be implemented.
  • FIG. 2 is an enlarged representation of the nebulizer diagram shown in FIG. 1 .
  • FIG. 3 shows a cross-sectional view of a generally known aerosol generator, as described in WO 2001/032246.
  • FIG. 4 is an image of a PARI eFlow® nebulizer, modified for use with the aminoglycoside formulations described herein, and a blown up diagram of the nebulizer's membrane.
  • FIG. 5 is a cross-sectional computed tomography (CT) image showing a membrane having a relatively long nozzle portion.
  • CT computed tomography
  • FIG. 8 is a graph of the time period of aerosol generation upon complete emission of the liquid within the liquid reservoir (Nebulization time) as a function of the initial gas cushion within the liquid reservoir (V A ).
  • FIG. 10 is a graph of aerosol generation efficiency as a function of the negative pressure in the nebulizer.
  • FIG. 11 is a graph of the period of time for aerosol generation upon complete emission of the liquid (nebulization time) as a function of the ratio between the increased volume V RN of the liquid reservoir and the initial volume of liquid within the liquid reservoir (V L ) (V RN V L ).
  • FIG. 13 is a graph showing the FPF of aerosolized formulations as a function of the nebulization rate of the respective formulation.
  • FIG. 14 is a schematic of the system used for the recovery of aerosol for post-nebulization studies.
  • Staphylococcus e.g., S. aureus, S. auricularis, S. carnosus, S. epidermidis, S. lugdunensis
  • Methicillin -resistant Staphylococcus aureus MRSA
  • Streptococcus e.g., Streptococcus pneumoniae
  • Escherichia coli Klebsiella, Enterobacter
  • Serratia Haemophilus
  • Yersinia pestis Mycobacterium (e.g., nontuberculous mycobacterium).
  • the nontuberculous mycobacterial lung infection in one embodiment, 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 intracellulare ), M. conspicuum, M. kansasii, M. peregrinum, M. immunogenum, M. xenopi, M marinum, M. malmoense, M marinum, M mucogenicum, M nonchromogenicum, M.
  • 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
  • a cystic fibrosis patient is treated for a bacterial infection with one of the systems provided herein.
  • the bacterial infection is a lung infection due to Pseudomonas aeruginosa .
  • a patient is treated for a pulmonary infection associated with bronchiectasis with one of the systems provided herein.
  • “Prophylaxis,” as used herein, can mean complete prevention of an infection or disease, or 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 disease or its symptoms.
  • antibacterial is art-recognized and refers to the ability of the compounds of the present invention to prevent, inhibit or destroy the growth of microbes of bacteria. Examples of bacteria are provided above.
  • antimicrobial is art-recognized 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.
  • Effective amount means an amount of an aminoglycoside (e.g., amikacin) used in the present invention sufficient to result in the desired therapeutic response.
  • the effective amount of the formulation provided herein comprises both free and liposomal complexed aminoglycoside.
  • the liposomal complexed aminoglycoside in one embodiment, comprises aminoglycoside encapsulated in a liposome, or complexed with a liposome, or a combination thereof.
  • the aminoglycoside is selected from amikacin, apramycin, arbekacin, astromicin, capreomycin, dibekacin, framycetin, gentamicin, hygromycin B, isepamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodestreptomycin, ribostamycin, sisomicin, spectinomycin, streptomycin, tobramycin or verdamicin.
  • the aminoglycoside is selected from an aminoglycoside set forth in Table C, below.
  • the aminoglycoside is an aminoglycoside free base, or its salt, solvate, or other non-covalent derivative.
  • the aminoglycoside is amikacin.
  • suitable aminoglycosides used in the drug formulations of the present invention are pharmaceutically acceptable addition salts and complexes of drugs.
  • the present invention comprises each unique racemic compound, as well as each unique nonracemic compound.
  • both the cis (Z) and trans (E) isomers are within the scope of this invention.
  • each tautomeric form is contemplated as being included within the invention.
  • Amikacin in one embodiment, is present in the pharmaceutical formulation as amikacin base, or amikacin salt, for example, amikacin sulfate or amikacin disulfate.
  • a combination of one or more of the above aminoglycosides is used in the formulations, systems and methods described herein. In a further embodiment, the combination comprises amikacin.
  • the therapeutic response can be any response that a user (e.g., a clinician) will recognize as an effective response to the therapy.
  • the therapeutic response will generally be a reduction, inhibition, delay or prevention in growth of or reproduction of one or more bacterium, or the killing of one or more bacterium, as described above.
  • a therapeutic response may also be reflected in an improvement in pulmonary function, for example forced expiratory volume in one second (FEV 1 ). It is further within the skill of one of ordinary skill in the art to determine appropriate treatment duration, appropriate doses, and any potential combination treatments, based upon an evaluation of therapeutic response.
  • Liposomal dispersion refers to a solution or suspension comprising a plurality of liposomes.
  • aerosol is a gaseous suspension of liquid particles.
  • the aerosol provided herein comprises particles of the liposomal dispersion.
  • a “nebulizer” or an “aerosol generator” is a device that converts a liquid into an aerosol of a size that can be inhaled into the respiratory tract.
  • Pneumonic, ultrasonic, electronic nebulizers e.g., passive electronic mesh nebulizers, active electronic mesh nebulizers and vibrating mesh nebulizers are amenable for use with the invention if the particular nebulizer emits an aerosol with the required properties, and at the required output rate.
  • nebulizer The process of pneumatically converting a bulk liquid into small droplets is called atomization.
  • the operation of a pneumatic nebulizer requires a pressurized gas supply as the driving force for liquid atomization.
  • Ultrasonic nebulizers use electricity introduced by a piezoelectric element in the liquid reservoir to convert a liquid into respirable droplets.
  • Various types of nebulizers are described in Respiratory Care, Vol. 45, No. 6, pp. 609-622 (2000), the disclosure of which is incorporated herein by 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”.
  • FPF Protein particle fraction
  • Mass median diameter is determined by laser diffraction or impactor measurements, and is the average particle diameter by mass.
  • Mass median aerodynamic diameter is normalized regarding the aerodynamic separation of aqua aerosol droplets and is determined impactor measurements, e.g., the Anderson Cascade Impactor (ACI) or the Next Generation Impactor (NGI).
  • the gas flow rate in one embodiment, is 28 Liter per minute by the Anderson Cascade Impactor (ACI) and 15 Liter per minute by the Next Generation Impactor (NGI).
  • Geometric standard deviation or “GSD” is a measure of the spread of an aerodynamic particle size distribution.
  • the present invention provides a system for treating a pulmonary infection or providing prophylaxis against a pulmonary infection. Treatment is achieved via delivery of the aminoglycoside formulation by inhalation via nebulization.
  • the pharmaceutical formulation comprises an aminoglycoside agent, e.g., an aminoglycoside.
  • the pharmaceutical formulation is a liposomal dispersion.
  • the pharmaceutical formulation is a dispersion comprising a “liposomal complexed aminoglycoside” or an “aminoglycoside encapsulated in a liposome”.
  • a “liposomal complexed aminoglycoside” includes embodiments where the aminoglycoside (or combination of aminoglycosides) is encapsulated in a liposome, and includes any form of aminoglycoside composition where 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 where the aminoglycoside may be in the aqueous phase or the hydrophobic bilayer phase or at the interfacial headgroup region of the liposomal bilayer.
  • 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 a further embodiment, the lipid component consists essentially of electrically neutral lipids. In even a further embodiment, the lipid component consists of electrically neutral lipids, e.g., a sterol and a phospholipid.
  • liposomal complexed aminoglycoside embodiments include embodiments where the aminoglycoside is encapsulated in a liposome.
  • the liposomal complexed aminoglycoside describes any composition, solution or suspension where 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 where the aminoglycoside may be in the aqueous phase or the hydrophobic bilayer phase or at the interfacial headgroup region of the liposomal bilayer.
  • association in one embodiment, is measured by separation through a filter where lipid and lipid-associated drug is retained (i.e., in the retentate) and free drug is in the filtrate.
  • the formulations, systems and methods provided herein comprise a lipid-encapsulated or lipid-associated aminoglycoside agent.
  • 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.
  • the phospholipid is selected from: phosphatidylcholine (EPC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE), and phosphatidic acid (PA); the soya counterparts, soy phosphatidylcholine (SPC); SPG, SPS, SPI, SPE, and SPA; the hydrogenated egg and soya counterparts (e.g., HEPC, HSPC), phospholipids made up of ester linkages of fatty acids in the 2 and 3 of glycerol positions containing chains of 12 to 26 carbon atoms and different head groups in the 1 position of glycerol that include choline, glycerol, inositol, serine, ethanolamine, as well as the corresponding phosphatidic acids.
  • EPC phosphatidylcholine
  • PG phosphatidylgly
  • the pharmaceutical formulation includes dipalmitoylphosphatidylcholine (DPPC), a major constituent of naturally-occurring lung surfactant.
  • DPPC dipalmitoylphosphatidylcholine
  • the lipid component of the pharmaceutical formulation comprises DPPC and cholesterol, or consists essentially of DPPC and cholesterol, or consists of DPPC and cholesterol.
  • the DPPC and cholesterol have a mole ratio in the range of from about 19:1 to about 1:1, or about 9:1 to about 1:1, or about 4:1 to about 1:1, or about 2:1 to about 1:1, or about 1.86:1 to about 1:1.
  • the DPPC and cholesterol have a mole ratio of about 2:1 or about 1:1.
  • DPPC and cholesterol are provided in an aminoglycoside formulation, e.g., an aminoglycoside formulation.
  • lipids for use with the invention include, but are not limited to, dimyristoylphosphatidycholine (DMPC), dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidcholine (DPPC), dipalmitoylphosphatidylglycerol (DPPG), distearoylphosphatidylcholine (DSPC), distearoylphosphatidylglycerol (DSPG), dioleylphosphatidyl-ethanolamine (DOPE), mixed phospholipids such as palmitoylstearoylphosphatidyl-choline (PSPC), and single acylated phospholipids, for example, mono-oleoyl-phosphatidylethanolamine (MOPE).
  • DMPC dimyristoylphosphatidycholine
  • DMPG dimyristoylphosphatidylglycerol
  • DPPC dipalmitoylphosphatidcholine
  • DPPG dipalmito
  • the at least one lipid component comprises a sterol. In a further embodiment, the at least one lipid component 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, esters of cholesterol including cholesterol hemi-succinate, salts of cholesterol including cholesterol hydrogen sulfate and cholesterol sulfate, ergosterol, esters of ergosterol including ergosterol hemi-succinate, salts of ergosterol including ergosterol hydrogen sulfate and ergosterol sulfate, lanosterol, esters of lanosterol including lanosterol hemi-succinate, salts of lanosterol including lanosterol hydrogen sulfate, lanosterol sulfate and tocopherols.
  • the tocopherols can include tocopherols, esters of tocopherols including tocopherol hemi-succinates, salts of tocopherols including tocopherol hydrogen sulfates and tocopherol sulfates.
  • the term “sterol compound” includes sterols, tocopherols and the like.
  • At least one cationic lipid (positively charged lipid) is provided in the systems described herein.
  • the cationic lipids used can include ammonium salts of fatty acids, phospholids and glycerides.
  • the fatty acids include fatty acids of carbon chain lengths of 12 to 26 carbon atoms that are either saturated or unsaturated.
  • Some specific examples include: myristylamine, palmitylamine, laurylamine and stearylamine, dilauroyl ethylphosphocholine (DLEP), dimyristoyl ethylphosphocholine (DMEP), dipalmitoyl ethylphosphocholine (DPEP) and distearoyl ethylphosphocholine (DSEP), N-(2,3-di-(9-(Z)-octadecenyloxy)-prop-1-yl-N,N,N-trimethylammoniu-m chloride (DOTMA) and 1,2-bis(oleoyloxy)-3-(trimethylammonio) propane (DOTAP).
  • DLEP dilauroyl ethylphosphocholine
  • DMEP dimyristoyl ethylphosphocholine
  • DPEP dipalmitoyl ethylphosphocholine
  • DSEP distearoyl ethylphosphocholine
  • At least one anionic lipid (negatively charged lipid) is provided in the systems described herein.
  • the negatively-charged lipids which can be used include phosphatidyl-glycerols (PGs), phosphatidic acids (PAs), phosphatidylinositols (PIs) and the phosphatidyl serines (PSs). Examples include DMPG, DPPG, DSPG, DMPA, DPPA, DSPA, DMPI, DPPI, DSPI, DMPS, DPPS and DSPS.
  • phosphatidylcholines such as DPPC, aid in the uptake of the aminoglycoside agent by the cells in the lung (e.g., the alveolar macrophages) and helps to maintain the aminoglycoside agent in the lung.
  • the negatively charged lipids such as the PGs, PAs, PSs and PIs, in addition to reducing particle aggregation, are thought to play a role in the sustained activity characteristics of the inhalation formulation as well as in the transport of the formulation across the lung (transcytosis) for systemic uptake.
  • the sterol compounds without wishing to be bound by theory, are thought to affect the release characteristics of the formulation.
  • Liposomes are completely closed lipid bilayer membranes containing an entrapped aqueous volume. Liposomes may be unilamellar vesicles (possessing a single membrane bilayer) or multilamellar vesicles (onion-like structures characterized by multiple membrane bilayers, each separated from the next by an aqueous layer) or a combination thereof.
  • the bilayer is composed of two lipid monolayers having a hydrophobic “tail” region and a hydrophilic “head” region.
  • the structure of the membrane bilayer is such that the hydrophobic (nonpolar) “tails” of the lipid monolayers orient toward the center of the bilayer while the hydrophilic “heads” orient towards the aqueous phase.
  • Liposomes can be produced by a variety of methods (see, e.g., Cullis et al. (1987)). In one embodiment, one or more of the methods described in U.S. Patent Application Publication No. 2008/0089927 are used herein to produce the aminoglycoside encapsulated lipid formulations (liposomal dispersion). The disclosure of U.S. Patent Application Publication No. 2008/0089927 is incorporated by reference in its entirety for all purposes.
  • 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 to prior to mixing with the lipid, during mixing with the lipid or after mixing with the lipid. Additionally, the coacervate can be a coacervate of the active agent.
  • the liposomal dispersion is formed by dissolving one or more lipids in an organic solvent forming a lipid solution, and the aminoglycoside coacervate forms from mixing an aqueous solution of the aminoglycoside with the lipid solution.
  • the organic solvent is ethanol.
  • the one or more lipids comprise a phospholipid and a sterol.
  • liposomes are produces by sonication, extrusion, homogenization, swelling, electroformation, inverted emulsion or a reverse evaporation method.
  • Bangham's procedure J. Mol. Biol. (1965)
  • MMVs multilamellar vesicles
  • Lenk et al. U.S. Pat. Nos. 4,522,803, 5,030,453 and 5,169,637
  • Fountain et al. U.S. Pat. No. 4,588,578
  • Cullis et al. U.S. Pat. No.
  • Unilamellar vesicles can be produced from MLVs by a number of techniques, for example, the extrusion techniques of U.S. Pat. No. 5,008,050 and U.S. Pat. No. 5,059,421. Sonication and homogenization cab be so 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)).
  • the liposome preparation of Bangham et al. involves suspending phospholipids in an organic solvent which is then evaporated to dryness leaving a phospholipid film on the reaction vessel. Next, an appropriate amount of aqueous phase is added, the 60 mixture is allowed to “swell”, and the resulting liposomes which consist of multilamellar vesicles (MLVs) are dispersed by mechanical means.
  • MLVs multilamellar vesicles
  • LUVs large unilamellar vesicles
  • reverse phase evaporation infusion procedures, and detergent dilution
  • liposomes for use in the pharmaceutical formulations provided herein.
  • a review of these and other methods for producing liposomes may be found in the text Liposomes, Marc Ostro, ed., Marcel Dekker, Inc., New York, 1983, Chapter 1, which is incorporated herein by reference. See also Szoka, Jr. et al., (Ann. Rev. Biophys. Bioeng. 9, 1980, p. 467), which is also incorporated herein by reference in its entirety for all purposes.
  • liposomes include those that form reverse-phase evaporation vesicles (REV), U.S. Pat. No. 4,235,871.
  • REV reverse-phase evaporation vesicles
  • Another class of liposomes that may be used is characterized as having substantially equal lamellar solute distribution.
  • This class of liposomes is denominated as stable plurilamellar vesicles (SPLV) as defined in U.S. Pat. No. 4,522,803, and includes monophasic vesicles as described in U.S. Pat. No. 4,588,578, and frozen and thawed multilamellar vesicles (FATMLV) as described above.
  • SPLV stable plurilamellar vesicles
  • FATMLV frozen and thawed multilamellar vesicles
  • sterols and their water soluble derivatives such as cholesterol hemisuccinate have been used to form liposomes; see, e.g., U.S. Pat. No. 4,721,612. Mayhew et al., PCT Publication No. WO 85/00968, described a method for reducing the toxicity of drugs by encapsulating them in liposomes comprising alpha-tocopherol and certain derivatives thereof. Also, a variety of tocopherols and their water soluble derivatives have been used to form liposomes, see PCT Publication No. 87/02219.
  • the pharmaceutical formulation in one embodiment, pre-nebulization, comprises liposomes with a mean diameter, that is measured by a light scattering method, of approximately 0.01 microns to approximately 3.0 microns, for example, in the range about 0.2 to about 1.0 microns.
  • the mean 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, about 230 nm to about 280 nm, about 240 nm to about 280 nm, about 250 nm to about 280 nm or about 260 nm to about 280 nm.
  • the sustained activity profile of the liposomal product can be regulated by the nature of the lipid membrane and by inclusion of other excipients in the composition.
  • the liposomal entrapment of the aminoglycoside e.g., the aminoglycoside amikacin
  • the L/D ratio in liposomes provided herein is 0.7 or about 0.7 (w/w).
  • the liposomes provided herein are small enough to effectively penetrate a bacterial biofilm (e.g., Pseudomonas biofilm).
  • the mean diameter of the liposomes, as measured by light scattering is about 260 to about 280 nm.
  • the system provided herein comprises an aminoglycoside formulation, for example, an amikacin formulation, e.g., amikacin base formulation.
  • the amount of aminoglycoside provided 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.
  • the amount of aminoglycoside provided 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 from about 550 mg to about 600 mg.
  • the amount of aminoglycoside administered to the subject is about 560 mg and is provided in an 8 mL formulation. In one embodiment, the amount of aminoglycoside administered to the subject is about 590 mg and is provided in an 8 mL formulation. In one embodiment, the amount of aminoglycoside administered to the subject is about 600 mg and is provided in an 8 mL formulation. In one embodiment, the aminoglycoside is amikacin and the amount of amikacin provided 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.
  • the aminoglycoside is amikacin and the amount of amikacin provided in 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 subject is about 560 mg, and is provided in an 8 mL formulation. In one embodiment, the aminoglycoside is amikacin and the amount of amikacin administered to the subject is about 590 mg, and is provided in an 8 mL formulation. In one embodiment, the aminoglycoside is amikacin and the amount of aminoglycoside administered to the subject is about 600 mg and is provided in an 8 mL formulation.
  • the system provided herein comprises an about 8 mL liposomal amikacin formulation.
  • the density of the liposomal amikacin formulation is about 1.05 gram/mL; and in one embodiment, approximately 8.4 grams of the liposomal amikacin formulation per dose is present in the system of the invention.
  • the entire volume of the formulation is administered to a subject in need thereof.
  • the pharmaceutical formulation provided herein comprises at least one aminoglycoside, at least one phospholipid and a sterol. In a further embodiment, the pharmaceutical formulation comprises an aminoglycoside, DPPC and cholesterol. In one embodiment, the pharmaceutical formulation is the formulation provided in Table 2, below.
  • the lipid to drug ratio is fixed, and as amikacin concentration is increased (and therefore lipid concentration is increased, since the ratio of the two is fixed, for example at ⁇ 0.7:1), the viscosity of the solution also increases, which slows nebulization time.
  • the aminoglycoside prior to nebulization of the aminoglycoside formulation, about 70% to about 100% of the aminoglycoside present in the formulation is liposomal complexed.
  • the aminoglycoside is an aminoglycoside.
  • the aminoglycoside is amikacin.
  • prior to nebulization about 80% to about 99%, or about 85% to about 99%, or about 90% to about 99% or about 95% to about 99% or about 96% to about 99% of the aminoglycoside present in the formulation is liposomal complexed.
  • the aminoglycoside is amikacin or tobramycin.
  • the aminoglycoside is amikacin.
  • prior to nebulization about 98% of the aminoglycoside present in the formulation is liposomal complexed.
  • the aminoglycoside is amikacin or tobramycin.
  • the aminoglycoside is amikacin.
  • the aminoglycoside agent upon nebulization, about 20% to about 50% of the liposomal complexed aminoglycoside agent is released, due to shear stress on the liposomes.
  • the aminoglycoside agent is an amikacin.
  • the aminoglycoside agent upon nebulization, about 25% to about 45%, or about 30% to about 40% of the liposomal complexed aminoglycoside agent is released, due to shear stress on the liposomes.
  • the aminoglycoside agent is amikacin.
  • the present invention provides methods and systems for treatment of lung infections by inhalation of a liposomal aminoglycoside formulation via nebulization.
  • the formulation in one embodiment, is administered via a nebulizer, which provides an aerosol mist of the formulation for delivery to the lungs of a subject.
  • the nebulizer described herein generates an aerosol (i.e., achieves a total output rate) of the aminoglycoside pharmaceutical formulation at a rate greater than about 0.53 g per minute, greater than about 0.54 g per minute, greater than about 0.55 g per minute, greater than about 0.58 g per minute, greater than about 0.60 g per minute, greater than about 0.65 g per minute or greater than about 0.70 g per minute.
  • the nebulizer described herein generates an aerosol (i.e., achieves a total output rate) of the aminoglycoside pharmaceutical formulation at about 0.53 g per minute to about 0.80 g per minute, at about 0.53 g per minute to about 0.70 g per minute, about 0.55 g per min to about 0.70 g per minute, about 0.53 g per minute to about 0.65 g per minute, or about 0.60 g per minute to about 0.70 g per minute.
  • the nebulizer described herein generates an aerosol (i.e., achieves a total output rate) of the aminoglycoside pharmaceutical formulation at about 0.53 g per minute to about 0.75 g per minute, about 0.55 g per min to about 0.75 g per minute, about 0.53 g per minute to about 0.65 g per minute, or about 0.60 g per minute to about 0.75 g per minute.
  • the liposomes in the pharmaceutical formulation leak drug.
  • the amount of liposomal complexed aminoglycoside post-nebulization is about 45% to about 85%, or about 50% to about 80% or about 51% to about 77%. These percentages are also referred to herein as “percent associated aminoglycoside post-nebulization”.
  • the liposomes comprise an aminoglycoside, e.g., amikacin.
  • the percent associated aminoglycoside post-nebulization is from about 60% to about 70%.
  • the aminoglycoside is amikacin.
  • the percent associated aminoglycoside post-nebulization is about 67%, or about 65% to about 70%.
  • the aminoglycoside is amikacin.
  • the percent associated aminoglycoside post-nebulization is measured by reclaiming the aerosol from the air by condensation in a cold-trap, and the liquid is subsequently assayed for free and encapsulated aminoglycoside (associated aminoglycoside).
  • the MMAD of the aerosol of the pharmaceutical formulation is less than 4.9 ⁇ m, less than 4.5 ⁇ m, less than 4.3 ⁇ m, less than 4.2 ⁇ m, less than 4.1 ⁇ m, less than 4.0 ⁇ m or less than 3.5 ⁇ m, as measured by the 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.
  • the MMAD of the aerosol of the pharmaceutical formulation is about 1.0 ⁇ m to about 4.2 ⁇ m, about 3.2 ⁇ m to about 4.2 ⁇ m, about 3.4 ⁇ m to about 4.0 ⁇ m, about 3.5 jam to about 4.0 ⁇ m or about 3.5 ⁇ m to about 4.2 ⁇ m, as measured by the ACI.
  • the MMAD of the aerosol of the pharmaceutical formulation is about 2.0 ⁇ m to about 4.9 ⁇ m, about 4.4 ⁇ m to about 4.9 ⁇ m, about 4.5 ⁇ m to about 4.9 ⁇ m, or about 4.6 ⁇ m to about 4.9 ⁇ m, as measured by the NGI.
  • the nebulizer described herein generates an aerosol of the aminoglycoside pharmaceutical formulation at a rate greater than about 0.53 g per minute, greater than about 0.55 g per minute, or greater than about 0.60 g per minute or about 0.60 g per minute to about 0.70 g per minute.
  • the FPF of the aerosol is greater than or equal to about 64%, as measured by the ACI, greater than or equal to about 70%, as measured by the ACI, greater than or equal to about 51%, as measured by the NGI, or greater than or equal to about 60%, as measured by the NGI.
  • the system provided herein comprises a nebulizer selected from an electronic mesh nebulizer, pneumonic (jet) nebulizer, ultrasonic nebulizer, breath-enhanced nebulizer and breath-actuated nebulizer.
  • a nebulizer selected from an electronic mesh nebulizer, pneumonic (jet) nebulizer, ultrasonic nebulizer, breath-enhanced nebulizer and breath-actuated nebulizer.
  • the nebulizer is portable.
  • a pressurized gas supply is used as the driving force for liquid atomization in a pneumatic nebulizer.
  • Compressed gas is delivered, which causes a region of negative pressure.
  • the solution to be aerosolized is then delivered into the gas stream and is sheared into a liquid film. This film is unstable and breaks into droplets because of surface tension forces. Smaller particles, i.e., particles with the MMAD and FPF properties described above, can then be formed by placing a baffle in the aerosol stream.
  • gas and solution is mixed prior to leaving the exit port (nozzle) and interacting with the baffle. In another embodiment, mixing does not take place until the liquid and gas leave the exit port (nozzle).
  • the gas is air, O 2 and/or CO 2 .
  • droplet size and output rate can be tailored in a pneumonic nebulizer.
  • the gas velocity and/or pharmaceutical formulation velocity is modified to achieve the output rate and droplet sizes of the present invention.
  • the flow rate of the gas and/or solution can be tailored to achieve the droplet size and output rate of the invention.
  • an increase in gas velocity in one embodiment, decreased droplet size.
  • the ratio of pharmaceutical formulation flow to gas flow is tailored to achieve the droplet size and output rate of the invention.
  • an increase in the ratio of liquid to gas flow increases particle size.
  • a pneumonic nebulizer output rate is increased by increasing the fill volume in the liquid reservoir. Without wishing to be bound by theory, the increase in output rate may be due to a reduction of dead volume in the nebulizer.
  • Nebulization time in one embodiment, is reduced by increasing the flow to power the nebulizer. See, e.g., Clay et al. (1983). Lancet 2, pp. 592-594 and Hess et al. (1996). Chest 110, pp. 498-505.
  • a reservoir bag is used to capture aerosol during the nebulization process, and the aerosol is subsequently provided to the subject via inhalation.
  • the nebulizer provided herein includes a valved open-vent design. In this embodiment, when the patient inhales through the nebulizer, nebulizer output is increased. During the expiratory phase, a one-way valve diverts patient flow away from the nebulizer chamber.
  • the nebulizer provided herein is a continuous nebulizer. In other words, refilling the nebulizer with the pharmaceutical formulation while administering a dose is not needed. Rather, the nebulizer has at least an 8 mL capacity or at least a 10 mL capacity.
  • a vibrating mesh nebulizer is used to deliver the aminoglycoside formulation of the invention to a patient in need thereof.
  • the nebulizer membrane vibrates at an ultrasonic frequency of about 100 kHz to about 250 kHz, about 110 kHz to about 200 kHz, about 110 kHz to about 200 kHz, about 110 kHz to about 150 kHz.
  • the nebulizer membrane vibrates at a frequency of about 117 kHz upon the application of an electric current.
  • the nebulizer provided herein does not use an air compressor and therefore does not generate an air flow.
  • aerosol is produced by the aerosol head which enters the mixing chamber of the device. When the patient inhales, air enters the mixing chamber via one-way inhalation valves in 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 on the mouthpiece of the device. In one embodiment, the nebulizer continues to generate aerosol into the mixing chamber which is then drawn in by the subject on the next breath—and this cycle continues until the nebulizer medication reservoir is empty.
  • the present invention in one embodiment, is carried out with one of the aerosol generators (nebulizers) depicted in FIGS. 1 , 2 , 3 and 4 .
  • the systems of the invention in one embodiment, include a nebulizer described in European Patent Applications 11169080.6 and/or 10192385.2. These applications are incorporated by reference in their entireties.
  • FIG. 1 shows a therapeutic aerosol device 1 with a nebulizing chamber 2 , a mouthpiece 3 and a membrane aerosol generator 4 with an oscillating membrane 5 .
  • the oscillating membrane may, for example, be brought to oscillation by annular piezo elements (not shown), examples of which are described in WO 1997/29851.
  • the pharmaceutical formulation When in use, the pharmaceutical formulation is located on one side of the oscillating membrane 5 , see FIGS. 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 bottom of FIG. 1 , FIG. 2 , as an aerosol into the nebulizing chamber 2 .
  • the patient is able to breathe in the aerosol present in the nebulizing chamber 2 at the mouthpiece 3 .
  • the oscillating membrane 5 comprises a plurality of through holes. Droplets of the aminoglycoside formulation are generated when the aminoglycoside pharmaceutical formulation passes through the membrane.
  • the membrane is vibratable, a so called active electronic mesh nebulizer, for example the eFlow® nebulizer from PARI Pharma, HL100 nebulizer from Health and Life, or the Aeroneb Got from Aerogen (Novartis).
  • 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.
  • the membrane vibrates at a frequency of about 117 kHz upon the application of an electric current.
  • the membrane is fixed and the a further part of the fluid reservoir or fluid supply is vibratable, a so called passive electronic mesh nebulizer, for example the MicroAir Electronic Nebulizer Model U22 from Omron or the I-Neb I-neb AAD Inhalation System from Philips Respironics.
  • the length of the nozzle portion of the through holes formed in the membrane influences the total output rate (TOR) of the aerosol generator.
  • TOR total output rate
  • the nozzle portion is sufficiently short and small in diameter as compared to the upstream portion of the through hole. In a further embodiment, the length of the portions upstream of the nozzle portion within the through hole does not have a significant influence on the TOR.
  • the length of the nozzle portion influences the geometric standard deviation (GSD) of the droplet size distribution of the aminoglycoside pharmaceutical formulation.
  • GSD geometric standard deviation
  • Low GSDs characterize a narrow droplet size distribution (homogeneously sized droplets), which is advantageous for targeting aerosol to the respiratory system, for example for the treatment of bacterial infections (e.g., Pseudomonas or Mycobacteria) in cystic fibrosis patients, or the treatment of nontuberculosis mycobacteria, bronchiectasis (e.g., the treatment of cystic fibrosis or non- cystic fibrosis patients), Pseudomonas or Mycobacteria in patients.
  • bacterial infections e.g., Pseudomonas or Mycobacteria
  • nontuberculosis mycobacteria bronchiectasis
  • bronchiectasis e.g., the treatment of cystic fibros
  • the average droplet size in one embodiment is less than 5 ⁇ m, and has a GSD in a range of 1.0 to 2.2, or about 1.0 to about 2.2, or 1.5 to 2.2, or about 1.5 to about 2.2.
  • the system provided herein comprises a nebulizer which generates an aerosol of the aminoglycoside pharmaceutical formulation at a rate greater than about 0.53 g per minute, or greater than about 0.55 g per minute.
  • the nebulizer comprises a vibratable membrane having a first side for being in contact with the fluid and an opposite second side, from which the droplets emerge.
  • the membrane e.g., a stainless steel membrane
  • the membrane may be vibrated by means of a piezoelectric actuator or any other suitable means.
  • the membrane has a plurality of through holes penetrating the membrane in an extension direction from the first side to the second side.
  • the through holes may be formed as previously mentioned by a laser source, electroforming or any other suitable process.
  • the aminoglycoside pharmaceutical formulation passes the through holes from the first side to the second side to generate the aerosol at the second side.
  • Each of the through holes in one embodiment, comprises an entrance opening and an exit opening.
  • each of the through holes comprises a nozzle portion extending from the exit opening over a portion of the through holes towards the entrance opening.
  • the nozzle portion is defined by the continuous portion of the through hole in the extension direction comprising a smallest diameter of the through hole and bordered by a larger diameter of the through hole.
  • the larger diameter of the through hole is defined as that diameter that is closest to 3 times, about 3 times, 2 times, about 2 times, 1.5 times, or about 1.5 times, the smallest diameter.
  • the smallest diameter of the through hole in one embodiment, is the diameter of the exit opening. In another embodiment, the smallest diameter of the through hole is a diameter about 0.5 ⁇ , about 0.6 ⁇ , about 0.7 ⁇ , about 0.8 ⁇ or about 0.9 ⁇ the diameter of the exit opening.
  • the nebulizer provided herein comprises through holes in which the ratio of the total length of at least one of the through holes in the extension direction 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.
  • the nebulizer provided herein comprises through holes in which the ratio of the total length of the majority of through holes in the extension direction to the length of the respective nozzle portion of the through holes 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.
  • the extension ratios set forth above provide, in one embodiment, an increased total output rate, as compared to previously known nebulizers, and also provides a sufficient GSD.
  • the ratio configurations in one embodiment, achieve 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 at a low concentration, and therefore, a greater volume of the aminoglycoside pharmaceutical formulation must be administered in an acceptable time, e.g., one dosing session.
  • the nozzle portion terminates flush with the second side. Therefore, the length of the nozzle portion, in one embodiment, is defined as that portion starting from the second side towards the first side up to and bordered by the diameter that it is closest to about triple, about twice, about 2.5 ⁇ , or about 1.5 ⁇ the smallest diameter.
  • the smallest diameter in this embodiment, is the diameter of the exit opening.
  • the smallest diameter i.e., one border of the nozzle portion
  • the larger diameter of the through hole, located at the other border 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.
  • the smallest diameter is smaller than about 4.5 ⁇ m, smaller than about 4.0 ⁇ m, smaller than about 3.5 ⁇ m, or smaller than about 3.0 ⁇ m.
  • the total length of at least one through hole in the extension direction is at least about 50 ⁇ m, at least about 60 ⁇ m, at least about 70 ⁇ m, or at least about 80 ⁇ m. In a further embodiment, the total length of at least one of the plurality of through holes is at least about 90 ⁇ m. In one embodiment, the total length of a majority of the plurality of through holes in the extension direction is at least about 50 ⁇ m, at least about 60 ⁇ m, at least about 70 um, or at least about 80 ⁇ m. In a further embodiment, the total length of a majority of the plurality of through holes is at least about 90 ⁇ m.
  • the length of the nozzle portion in one embodiment, is less than about 25 ⁇ m, less than about 20 ⁇ m or less than about 15 ⁇ m.
  • the through holes are laser-drilled through holes formed in at least two stages, one stage forming the nozzle portion and the remaining stage(s) forming the remainder of the through holes.
  • the manufacturing methods used lead to a nozzle portion which 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.
  • the through holes are formed in an electroforming process.
  • the through holes have a first funnel-shaped portion at the first side and a second funnel-shaped portion at the second side with the nozzle portion in-between the first and the second funnel-shaped portions and defined between the exit opening and the larger diameter.
  • the total length of the through holes may as well be defined by the distances from the first side to the exit opening (smallest diameter) only.
  • the total output rate (TOR) may be further increased by increasing the number of through holes provided in the membrane.
  • an increase in number of through holes is achieved by increasing the active perforated surface of the membrane and maintaining the distance of the through holes relative to each other at the same level.
  • the number of through holes is increased by reducing the distance of the through holes relative to each other and maintaining the active area of the membrane.
  • a combination of the above strategies may be used.
  • the total output rate of the nebulizer described herein is increased by increasing the density of through holes in the membrane.
  • the average distance between through holes is about 70 ⁇ m, or about 60 ⁇ m, or about 50 ⁇ m.
  • 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.
  • the number of through holes described above increases the TOR, and the TOR is increased regardless of whether the nozzle parameters are implemented as described above.
  • the nebulizer provided herein comprises about 3,000 through holes.
  • the through holes are located in a hexagonal array, e.g., at about the center of the membrane (e.g., stainless steel membrane).
  • the average distance between through holes is about 70 ⁇ m.
  • FIG. 3 shows an aerosol generator (nebulizer) as disclosed in WO 2001/032246, which is hereby incorporated by 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 by means of the mouth piece 4 through the opening 41 .
  • the aerosol generator comprises a vibratable membrane 22 vibrated by means of a piezoelectric actuator 23 .
  • the vibratable membrane 22 has a first side 24 facing the fluid container 21 and a second opposite side 25 facing the mixing chamber 3 .
  • the first side 24 of the vibratable membrane 22 is in contact with the fluid contained in the fluid container 21 .
  • a plurality of through holes 26 penetrating the membrane from the first side 24 to the second side 25 are provided in the membrane 22 .
  • 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 is vibrated for generating the aerosol at the second side 25 and emitting it into the mixing chamber 3 .
  • This aerosol may then be drawn by inhalation of a patient from the mixing chamber 3 via the mouth piece 4 and its inhalation opening 41 .
  • FIG. 5 shows a cross-sectional computed tomography scan showing three of the through holes 26 of such a vibratable membrane 22 .
  • the through holes 26 of this particular embodiment are formed by laser drilling using three stages of different process parameters, respectively.
  • the portion 30 is formed in a first stage.
  • the portion 31 is formed in a second stage.
  • the nozzle portion 32 is formed in a third stage.
  • the length of the nozzle portion 32 is about 26 ⁇ m, whereas the portion 31 has a length of about 51 ⁇ m.
  • the first portion 30 has a length of about 24.5 ⁇ m.
  • 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 , that is in this particular example, about 101.5 ⁇ m.
  • the ratio of the total length of each through hole 26 in the extension direction E to the length of a respective one of the nozzle portions 32 in the extension direction E is approximately 3.9.
  • the first portion 30 has a length of about 27 ⁇ m, the portion 31 a length of about 55 ⁇ m and a nozzle portion a length of about 19 ⁇ m.
  • the total length of the through hole 26 is about 101 ⁇ m.
  • 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.
  • Both the vibratable membranes in FIGS. 5 and 6 were manufactured with 6,000 through holes 26 .
  • the below table (Table 3) indicates the mass median diameter (MMD), as determined by laser diffraction, of the particles emitted at the second side of the membrane, the time required for completely emitting a certain amount of liquid (Nebulization time) as well as the TOR.
  • the tests were performed with a liposomal formulation of amikacin.
  • Table 3 shows that the membrane 2 with the shorter nozzle portion provides for an increased TOR and a reduced nebulization time by 5.3 minutes, which is approximately 36% less as compared to the membrane 1.
  • Table 3 also shows that the MMD did not vary significantly for each membrane tested. This is in contrast to the differences in TOR observed for each membrane.
  • the nebulization time for the nebulizer described herein is reduced significantly as compared to prior art nebulizers, without affecting the droplet size, as measured by MMD.
  • membranes were manufactured having the nozzle portion further reduced, and with 3,000 through holes 26 (membranes 3 and 4, Table 3).
  • a membrane 3 was laser-drilled with a shorter nozzle portion
  • membrane 4 was manufactured using a shorter nozzle portion than membrane 3 .
  • Table 3 indicates that even with 3,000 holes (membrane 3 and 4 ) a reduction in the length of the nozzle portion results in an increased TOR compared to membrane 1 with 6,000 holes.
  • the comparison of the membrane 3 and 4 as compared to the membrane 2 further shows that a combination of a higher number of holes (6,000 as compared to 3,000) and a reduced length of the nozzle portion increases the TOR for the nebulizer.
  • the through holes shown in FIGS. 5 and 6 are substantially cylindrical or conical as compared to the funnel-shaped entrance and exit of electro-formed through holes, e.g., as disclosed in WO 01/18280.
  • the vibration of the membrane that is its vibration velocity, may be transferred to the pharmaceutical formulation over a larger area by means of friction when the through holes are substantially cylindrical or conical as compared to the funnel-shaped entrance and exit of electro-formed through holes.
  • the pharmaceutical formulation because of its own inertia, is then ejected from the exit openings of the through holes resulting in liquid jets collapsing to form the aerosol.
  • an electro-formed membrane comprises extremely bent surfaces of the through holes, the surface or area for transferring the energy from the membrane to the liquid is reduced.
  • the present invention may also be implemented in electro-formed membranes, wherein the nozzle portion is defined by the continuous portion of the through hole in the extension direction starting from the smallest diameter of the through hole towards the first side until it reaches a diameter 2 ⁇ or 3 ⁇ of the smallest diameter of the hole.
  • the total length of the through hole is measured from the smallest diameter to the first side.
  • 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 hence into the nebulizing chamber 2 , the elastic valve element 7 opens so that the exhaled air is able to escape from the interior of the therapeutic aerosol. On inhalation, ambient air flows through the nebulizing chamber 2 .
  • the nebulizing chamber 2 has an opening sealed (not shown) by a further elastic valve element (inhalation valve).
  • the elastic valve element opens so that the ambient air is able to enter into the nebulizing chamber and mixed with the aerosol and leave the interior of the nebulizing chamber 2 to be inhaled. Further description of this process is provided in U.S. Pat. No. 6,962,151, which is incorporated by reference in its entirety for all purposes.
  • the nebulizer shown in FIG. 2 comprises a cylindrical storage vessel 10 to supply a liquid that is fed to the membrane 5 .
  • the oscillating membrane 5 may be arranged in an end wall 12 of the cylindrical liquid reservoir 10 to ensure that the liquid poured into the liquid reservoir comes into direct contact with the membrane 5 when the aerosol generator is held in the position shown in FIG. 1 .
  • other methods may also be used to feed the liquid to the oscillating membrane without any change being necessary to the design of the device according to the invention for the generation of a negative pressure in the liquid reservoir.
  • the cylindrical liquid container 10 On the side facing the end wall 12 , the cylindrical liquid container 10 is open. The opening is used to pour the liquid into the liquid reservoir 10 . Slightly below the opening on the external surface 13 of the peripheral wall 14 there is a projection 15 which serves as a support when the liquid container is inserted in an appropriately embodied opening in a housing 35 .
  • the open end of the liquid container 10 is closed by a flexible sealing element 16 .
  • the sealing element 16 lies on the end of the peripheral wall 14 of the liquid container 10 and extends in a pot-shaped way into the interior of the liquid container 10 whereby a conically running wall section 17 is formed in the sealing element 16 and closed off by a flat wall section 18 of the sealing element 16 .
  • forces act via the flat wall section 18 on the sealing element 16 and so in one embodiment the flat wall section 18 is thicker than the other sections of the sealing element 16 .
  • On the perimeter of the flat wall section 18 there is a distance to the conical wall section 17 so that the conical wall section 17 may be folded when the flat wall section 18 is moved upwards, relative to the representation in FIG. 2 .
  • the aerosol generator 4 comprises a slidable sleeve 21 equipped with an opening of this type which is substantially a hollow cylinder open on one side.
  • the opening for the attachment of the sealing element 16 is embodied in an end wall of the slidable sleeve 21 .
  • the end wall of the slidable sleeve 21 containing the opening lies on the flat sealing element wall section 18 .
  • the latching of the truncated cone 19 into the slidable sleeve enables forces to be transmitted from the slidable sleeve 21 onto the flat wall section 18 of the sealing element 16 so that the sealing section 18 follows the movements of the slidable sleeve 21 in the direction of the central longitudinal axis of the liquid container 10 .
  • the slidable sleeve 21 may be seen as a slidable element, which may, for example, also be implemented as a slidable rod which may be stuck-on or inserted in a drill hole.
  • Characteristic of the slidable element 21 is the fact that it may be used to apply a substantially linearly directed force onto the flat wall element 18 of the sealing element 16 .
  • the decisive factor for the mode of operation of the aerosol generator according to the invention is the fact that a slidable element transmits a linear movement onto 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 a negative pressure to be generated in the liquid reservoir 10 .
  • the slidable sleeve 21 is open on the end facing the drill hole for the truncated cone but at least two diametrically opposite lugs 22 and 23 protrude radially into the interior of the slidable sleeve 21 .
  • a collar 24 encircling the slidable sleeve extends radially outwards. While the collar 24 is used as a support for the slidable sleeve 21 in the position shown in FIG. 5 , the projections 22 and 23 protruding into the interior of the slidable sleeve 21 are used to absorb the forces acting on the slidable sleeve 21 in particular parallel to the central longitudinal axis. In one embodiment, these forces are generated by means of two spiral grooves 25 which are located on the outside of the peripheral wall of a rotary sleeve 26 .
  • the rotary sleeve 26 is also a cylinder open on one side whereby the open end is arranged in the slidable sleeve 21 and is hence facing the truncated cone 19 enabling the truncated cone 19 to penetrate the rotary sleeve 26 .
  • the rotary sleeve 26 is arranged in the slidable sleeve 21 in such a way that the projections 22 and 23 lie in the spiral grooves 25 .
  • the inclination of the spiral groove 25 is designed so that, when the rotary sleeve 26 is rotated in relation to the slidable 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 hence on the slidable sleeve 21 .
  • This force displaces the slidable sleeve 21 in the direction of the central longitudinal axis so that the sealing element 16 which is latched into the slidable sleeve's drill hole by means of the truncated cone is also substantially displaced parallel to the central longitudinal axis.
  • the rotary sleeve 26 is embodied in one piece with a handle 27 whose size is selected to enable the user to rotate the handle 27 , and hence the rotary sleeve 26 , manually without great effort.
  • the handle 27 substantially has the shape of a flat cylinder or truncated cone which is open on one side so that a peripheral gripping area 28 is formed on the external periphery of the handle 27 which is touched by the user's hand to turn the handle 27 .
  • the angle of rotation lies within a range from 45 to 360 degrees. This embodiment allows for the ease of handling of the device according to the invention and the therapeutic aerosol generator equipped therewith.
  • the aerosol generator described here has a bearing sleeve 29 for bearing the slidable sleeve 21 , which substantially comprises a flat cylinder open on one side.
  • the diameter of the peripheral wall 30 of the bearing sleeve 29 is smaller than the internal diameter of the handle 27 and, in the example of an embodiment described, is aligned on the internal diameter of a cylindrical latching ring 31 which is provided concentrically to the gripping area 28 of the handle 27 but with a smaller diameter on the side of the handle 27 on which the rotary sleeve 26 is also arranged.
  • a peripheral latching edge 32 which may be brought into engagement with latching lugs 33 situated at intervals on the peripheral wall 30 of the bearing sleeve 29 .
  • This allows the handle 27 to be located on the bearing sleeve 29 whereby, as shown in FIG. 5 , the handle 27 is placed on the open end of the bearing sleeve 29 and the latching edge 32 is interlatched with the latching lugs 33 .
  • an opening is provided in the centre of the sealed end of the bearing sleeve 29 in which the slidable sleeve 21 is arranged, as may be identified in FIG. 2 .
  • the collar 24 of the slidable sleeve 21 lies in the position shown in FIG. 2 on the surface of the end wall of the bearing sleeve 29 facing the handle.
  • Extending into the bearing opening are two diametrically opposite projections 51 and 52 , which protrude into two longitudinal grooves 53 and 54 on the peripheral surface of the slidable sleeve 21 .
  • the longitudinal grooves 53 and 54 run parallel to the longitudinal axis of the slidable sleeve 21 .
  • the guide projections 51 and 52 and the longitudinal grooves 53 and 54 provide anti-rotation locking for the slidable sleeve 21 so that the rotational movement of the rotary sleeve 26 results not in rotation but in the linear displacement of the slidable sleeve 21 .
  • this ensures that the slidable sleeve 21 is held in the combination of the handle 27 and the bearing sleeve 29 in an axially displaceable way but locked against rotation.
  • the rotary sleeve 26 also rotates in relation to the slidable sleeve 21 whereby the sliding projections 22 and 23 move along the spiral grooves 25 . This causes the slidable sleeve 21 to be displaced in an axial direction in the opening of the bearing sleeve 29 .
  • the guide projections 51 and 52 are not present in the aerosol generator, and the truncated cone 19 , the cylinder sections 20 of the sealing elements 16 and the large-area support for the slidable sleeve 21 holding the truncated cone on the flat sealing element section 18 achieves anti-rotation locking of the slidable sleeve 21 by means of friction.
  • the sealing element 16 is fixed so it is unable to rotate in relation to the bearing sleeve 29 .
  • annular first sealing lip 34 concentric to the opening holding the slidable sleeve.
  • the diameter of the first sealing lip 34 corresponds to the diameter of the peripheral wall 14 of the liquid container 10 .
  • this ensures that the first sealing lip 34 presses the sealing element 16 on the end of the peripheral wall against the liquid reservoir 10 in such a way that the liquid reservoir 10 is sealed.
  • the first sealing lip 34 may also fix the sealing element 16 so that it is unable to rotate in relation to the liquid reservoir 10 and the bearing sleeve 29 .
  • excessive force need not be applied in order to ensure that the aforesaid components of the device are unable to rotate in relation to each other.
  • the forces required are generated at least to some extent by means of an interaction between the handle 27 and the housing 35 in which the pharmaceutical formulation reservoir is embodied as one piece or in which the pharmaceutical formulation (liquid) reservoir 10 is inserted as shown in FIG. 2 .
  • the pharmaceutical formulation reservoir 10 inserted in the casing with the peripheral projection 15 lies at intervals on a support 36 in the housing 35 which extends radially into the interior of the housing 35 . This allows the liquid reservoir 10 to be easily removed from the housing 35 for purposes of cleaning.
  • support is only provided at intervals, and therefore, openings are provided for ambient air when the patient inhales, described in more detail below.
  • FIG. 2 Identifiable in FIG. 2 is the rotary lock, which is implemented by means of the handle 27 on the one hand and the housing 35 on the other. Shown are the locking projections 62 and 63 on the housing 35 .
  • the rotary lock there are no special requirements with regard to the design of the rotary lock as far as the device according to invention is concerned for the generation of the negative pressure in the liquid reservoir 10 .
  • the liquid reservoir 10 is configured to have a volume V RN of at least 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 amount of 8 mL of liquid (e.g., aminoglycoside pharmaceutical formulation) to be emitted in the form of an aerosol is contained in (filled or poured into) the liquid reservoir 10 , an air cushion of 8 mL or about 8 mL is provided. That is, the ratio of the volume V RN to the initial volume of liquid V L within the liquid reservoir 10 is at least 2.0 and the ratio between the volume V A of a gas and V L of the liquid is at least 1.0. It has been shown that a liquid reservoir having a volume V RN of about 15.5 mL, about 19.5 mL and about 22.5 mL are efficient, and that efficiency increases with the increase in V RN .
  • liquid e.g., aminoglycoside
  • the ratio between V RN and V L is at least 2.0, at least about 2.0, at least 2.4, at least about 2.4, at least 2.8 or at least about 2.8. In one embodiment, the ratio between V A and V L 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 ratio between V A and V L 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.
  • 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 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 air cushion is at least about 11 mL or at least about 14 mL.
  • the volume of the air cushion is from about 6 mL to about 15 mL, and the ratio between V RN and V L is at least about 2.0 to at least about 3.0. In a further embodiment, the between V RN and V L is at least about 2.0 to about at least about 2.8.
  • 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.
  • the ratio of the volume V RN to the initial volume of liquid V L is at least 2.0. Theoretically an unlimited enlargement of the increased volume V RN of the liquid reservoir 10 will result in a nearly stable negative pressure range. In one embodiment, the ratio of the volume V RN to the initial volume of liquid V L is within the range between 2.0 and 4.0 and in a further embodiment is between 2.4 and 3.2. Two examples of the ratio ranges (V RN /V L ) for different initial volume of liquid V L between 4 mL and 8 mL are given in Table 4, below.
  • the systems provided herein may be used to treat a variety of pulmonary infections in subjects in need thereof.
  • pulmonary infections such as in cystic fibrosis patients
  • infections caused by the following bacteria are treatable with the systems and formulations provided herein: Pseudomonas (e.g., P. aeruginosa, P. paucimobilis, P. putida, P. fluorescens, and P. acidovorans ), Burkholderia (e.g., B. pseudomallei, B. cepacia, B. cepacia complex, B. dolosa, B. fungorum, B. gladioli, B. multivorans, B.
  • Pseudomonas e.g., P. aeruginosa, P. paucimobilis, P. putida, P. fluorescens, and P. acidovorans
  • Burkholderia e.g., B. pseudomallei, B. cepacia, B. ce
  • MRSA Methicillin -resistant Staphylococcus aureus
  • Streptococcus e.g., Streptococcus pneumoniae
  • Escherichia coli Klebsiella, Enterobacter
  • Serratia Haemophilus
  • Yersinia pestis Mycobacterium, nontuberculous mycobacterium (e.g., 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.
  • MRSA Methicillin -resistant Staphylococcus aureus
  • Streptococcus e.g., Streptococcus pneumoniae
  • Escherichia coli Klebsiella, Enterobacter
  • Serratia Haemophilus
  • M conspicuum M. kansasii, M peregrinum, M. immunogenum, M. xenopi, M marinum, M. malmoense, M marinum, M mucogenicum, M nonchromogenicum, M. scrofulaceum, M simiae, M smegmatis, M szulgai, M terrae, M terrae complex, M haemophilum, M. genavense, M. asiaticum, M shimoidei, M gordonae, M. nonchromogenicum, M triplex, M lentiflavum, M celatum, M. fortuitum, M. fortuitum complex ( M. fortuitum and M chelonae )).
  • the systems described herein are used to treat an infection caused by a nontuberculous mycobacterial infection.
  • the systems described herein are used to treat an infection caused by Pseudomonas aeruginosa, Mycobacterium abscessus, Mycobaterium avium or M avium complex.
  • a patient with cystic fibrosis is treated for a Pseudomonas aeruginosa , Mycobacterium abscessus , Mycobaterium avium , or Mycobaterium avium complex infection with one or more of the systems described herein.
  • the Mycobaterium avium infection is Mycobacterium avium subsp. hominissuis.
  • a patient with cystic fibrosis is treated for a pulmonary infection with one of the systems provided herein.
  • the pulmonary infection is a Pseudomonas infection.
  • the Pseudomonas infection is P. aeruginosa .
  • the aminoglycoside in the system is amikacin.
  • the system provided herein is used for the treatment or prophylaxis of Pseudomonas aeruginosa, Mycobacterium abscessus, Mycobaterium avium or Mycobaterium avium complex lung infection in a cystic fibrosis patient or a non-cystic fibrosis patient.
  • the system provided herein comprises a liposomal aminoglycoside formulation.
  • the aminoglycoside is selected from amikacin, apramycin, arbekacin, astromicin, capreomycin, dibekacin, framycetin, gentamicin, hygromycin B, isepamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodestreptomycin, ribostamycin, sisomicin, spectinomycin, streptomycin, tobramycin, verdamicin or a combination thereof.
  • the aminoglycoside is amikacin, e.g., amikacin sulfate.
  • FIG. 7 An obstacle to treating infectious diseases such as Pseudomonas aeruginosa , the leading cause of chronic illness in cystic fibrosis patients is drug penetration within the sputum/biofilm barrier on epithelial cells ( FIG. 7 ).
  • the donut shapes represent liposomal/complexed aminoglycoside
  • the “+” symbol represents free aminoglycoside
  • the “ ⁇ ” symbol mucin, alginate and DNA
  • the solid bar symbol represents Pseudomonas aeruginosa .
  • This barrier comprises both colonized and planktonic P.
  • the negative charge binds up and prevents penetration of positively charged drugs such as aminoglycosides, rendering them biologically ineffective (Mendelman et al., 1985).
  • entrapment of aminoglycosides within liposomes or lipid complexes shields or partially shields the aminoglycosides from non-specific binding to the sputum/biofilm, allowing for liposomes or lipid complexes (with entrapped aminoglycoside) to penetrate ( FIG. 7 ).
  • a patient is treated for nontuberculous mycobacteria lung infection with one of the systems provided herein.
  • the system provided herein comprises a liposomal amikacin formulation.
  • system provided herein is used for the treatment or prophylaxis of one or more bacterial infections in a cystic fibrosis patient.
  • system provided herein comprises a liposomal aminoglycoside formulation.
  • aminoglycoside is amikacin.
  • system provided herein is used for the treatment or prophylaxis of one or more bacterial infections in a patient with bronchiectasis.
  • system provided herein comprises a liposomal aminoglycoside formulation.
  • aminoglycoside is amikacin or amikacin sulfate.
  • system provided herein is used for the treatment or prophylaxis of Pseudomonas aeruginosa lung infections in non-CF bronchiectasis patients.
  • system provided herein comprises a liposomal aminoglycoside formulation.
  • aminoglycoside is amikacin.
  • the present invention provides aminoglycoside formulations administered via inhalation.
  • the MMAD of the aerosol is about 3.2 ⁇ m to about 4.2 ⁇ m, as measured by the Anderson Cascade Impactor (ACI), or about 4.4 ⁇ m to about 4.9 ⁇ m, as measured by the Next Generation Impactor (NGI).
  • ACI Anderson Cascade Impactor
  • NTI Next Generation Impactor
  • the nebulization time of an effective amount of an aminoglycoside formulation provided herein is less than 20 minutes, less than 18 minutes, less than 16 minutes or less than 15 minutes. In one embodiment, the nebulization time of 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 of an effective amount of an aminoglycoside formulation provided herein is about 13 minutes.
  • the formulation described herein is administered once daily to a patient in need thereof.
  • the aerosol generator was an investigational eFlow® nebulizer, modified for use with liposomal aminoglycoside formulations provided herein, of Pari Pharma GmbH, Germany.
  • a first aerosol generator had an initial volume of the liquid reservoir V RI of 13 mL (A), a second one of 17 mL (B), a third one of 22 mL (C) and a fourth one of 20 mL (D). That is the increased volume V RN of the first one had 15.5 mL, the second one 19.5 mL, the third 24.5 mL and the fourth 22.5 mL.
  • FIG. 9 shows experimental data comparing the negative pressure range during the aerosol generation time for a liquid reservoir (C) having a volume V RN of 24.5 mL and a liquid reservoir (A) having a volume V RN of 15.5 mL.
  • the initial amount of amikacin formulation V L was 8 mL and the initial negative pressure was about 50 mbar.
  • the graph indicates that a larger air cushion prevents the negative pressure from increasing above a critical value of 300 mbar.
  • aerosol generator efficiency proportional to liquid output rate or total output rate
  • a liposomal amikacin formulation having a viscosity in the range of 5.5 to 14.5 mPa ⁇ s at sheer forces between 1.1 and 7.4 Pa (thixotrope) was used in the experiment.
  • the efficiency is optimum in a negative pressure range between 150 mbar and 300 mbar.
  • the efficiency decreases at a negative pressure below approximately 150 mbar and at a negative pressure of above 300 mbar.
  • the same liposomal amikacin formulation as in FIG. 8 was used in four different aerosol generators based on the modified eFlow®, wherein the first aerosol generator (A) is a modified eFlow® with an increased volume V RN of the liquid reservoir of 19.5 mL and filled with 8 mL of the liposomal amikacin formulation.
  • the first aerosol generator (A) is a modified eFlow® with an increased volume V RN of the liquid reservoir of 19.5 mL and filled with 8 mL of the liposomal amikacin formulation.
  • the second aerosol generator (B) had a reservoir with an increased volume V RN of 16 mL filled with 8 mL of the mentioned liposomal amikacin formulation
  • the third aerosol generator (C) one had an increased volume V RN of 24.5 mL, filled with 8 mL of the mentioned liquid.
  • the fourth aerosol generator had an increased volume V RN of the liquid reservoir of 22.5 mL, and was filled with 8 mL of the aforementioned liposomal amikacin formulation.
  • FIG. 11 shows experimental data of these four aerosol generators filled with 8 mL of the liposomal amikacin formulation.
  • the results show the aerosol generation time for complete emission of the liposomal amikacin formulation within the liquid reservoir in relation to the ratio of the increased volume of the liquid reservoir (V RN ) to the initial volume of liquid in the liquid reservoir before use (V L ).
  • FIG. 11 indicates that with the modified aerosol generator device (A) an aerosol generation time of approximately 16 minutes was required, whereas the aerosol generation time decreased with an increased ratio V RN /V L .
  • the data also shows that the aerosol generation time could be reduced by approximately 4 minutes to below 12 minutes with the third aerosol generator device (C).
  • Example 1 therefore indicates that a larger air cushion enables the operation of the aerosol generator for a longer time in an efficient negative pressure range so that the total aerosol generation time may significantly be reduced. Therefore, even large amounts of liquid such as 8 mL may be nebulized (emitted in form of aerosol) in a period of time below 12 minutes.
  • An Anderson Cascade Impactor was used for MMAD measurements and the nebulization work was conducted inside a ClimateZone chamber (Westech Instruments Inc., Ga.) to maintain temperature and relative civilization % during nebulization.
  • the climateZone was pre-set to a temperature of 18° C. and a relative civilization of 50%.
  • the ACI was assembled and loaded inside the ClimateZone.
  • a probe thermometer VWR dual thermometer was attached to the surface of ACI at stage 3 to monitor the temperature of ACI. Nebulization was started when the temperature of the ACI reached 18 ⁇ 0.5° C.
  • the nebulizer was either filled with 4 mL 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 (i.e., ⁇ 4 mL).
  • the nebulizate 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 difference in weight (amount nebulized) divided by the time interval.
  • ACI collection plates 0, 1, 2, 3, 4, 5, 6 and 7 were removed, and each was loaded into 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 dish to dissolve the formulation deposited on each plate.
  • Samples from plates 0, 1, 2, 3, 4, 5 and 6 were further diluted appropriately with 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 vial and 10 mL extraction solution was added, and the capped vial vortexed to dissolve any formulation deposited on it.
  • fine particle dose (FPD) was normalized to the volume of formulation nebulized in order to compare FPD across all experiments.
  • FPD fine particle dose
  • NGI Next Generation Impactor
  • Samples from cups 1, 2, 3, 4, 5, 6 and 7 were further diluted appropriately with mobile phase C for HPLC analysis.
  • Sample from MOC was directly analyzed by HPLC without any further dilution.
  • the NGI Filter was also transferred to a 20 mL vial and 10 mL extraction solution was added, and the capped vial vortexed to dissolve any formulation deposited on it. Liquid samples from the vial were filtered (0.2 micron) into HPLC vials for HPLC analysis.
  • the Induction port with connector was also rinsed with 10 mL extraction solution to dissolve the formulation deposited on it, and the sample was collected and analyzed by HPLC with 11 time dilution.
  • MMAD Based on the amikacin amount deposited on each stage of the impactor, MMAD, GSD and FPF were calculated.
  • FPD was normalized to the volume of formulation nebulized in order to compare FPD across all experiments.
  • FPD (normalized to the volume of formulation nebulized) was calculated according to the following equation:
  • Nebulization rate studies (grams of formulation nebulized per minute) were conducted in a biosafety cabinet (Model 1168, Type B2, FORMA Scientific). The assembled nebulizer (handset with mouth piece and aerosol head) was first weighed empty (W 1 ), then a certain volume of formulation was added and the nebulizer device was weighed again (W 2 ). The nebulizer and timer were started and the formulations nebulized were collected in a chilled impinger at a flow rate of ⁇ 8 L/min (see FIG. 14 for details of experimental setup). When there was no more aerosol observed, the timer was stopped. The nebulizer was weighed again (W 3 ), and the time of nebulization (t) was recorded. Total formulation nebulized was calculated as W 2 -W 3 and total drug residue after nebulization was calculated as W 3 -W 1 . The nebulization rate of formulation was calculated according to the following equation:
  • Example 3 The free and liposomal complexed amikacin in the nebulizate of Example 3 was measured. As mentioned in Example 3, the nebulizate was collected in a chilled impinger at a flow rate of 8 L/min ( FIG. 14 ).
  • the nebulizate collected in the impinger was rinsed with 1.5% NaCl and transferred to a 100 mL or 50-mL volumetric flask. The impinger was then rinsed several times with 1.5% NaCl in order to transfer all the formulation deposited in the impinger to the flask.
  • 0.5 mL of the diluted nebulizate inside the volumetric flask was taken and loaded to an Amicon® Ultra-0.5 mL 30K centrifugal filter device (regenerated cellulose, 30K MWCO, Millipore) and this device was centrifuged at 5000 G at 15° C. for 15 minutes.
  • the percent associated amikacin post-nebulization was calculated by the following equation:
  • 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 standards. The value obtained was 64 mg/mL amikacin.
  • the liposome sizes post-nebulization of the liposomal amikacin formulation aerosolized with twenty four nebulizer aerosol heads with 8 mL reservoir handsets were measured.
  • the pre-nebulization liposome mean diameter was approximately 285 nm (284.5 nm ⁇ 6.3 nm).
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9402845B2 (en) 2005-12-08 2016-08-02 Insmed Incorporated Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof
US9566234B2 (en) 2012-05-21 2017-02-14 Insmed Incorporated Systems for treating pulmonary infections
US9724301B2 (en) 2007-05-07 2017-08-08 Insmed Incorporated Methods of treating pulmonary disorders with liposomal amikacin formulations
US9737555B2 (en) 2007-05-07 2017-08-22 Insmed Incorporated Method of treating pulmonary disorders with liposomal amikacin formulations
US9827317B2 (en) 2002-10-29 2017-11-28 Insmed Incorporated Sustained release of antiinfectives
US9895385B2 (en) 2014-05-15 2018-02-20 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US9925205B2 (en) 2007-05-04 2018-03-27 Insmed Incorporated Compositions of multicationic drugs for reducing interactions with polyanionic biomolecules and methods of use thereof
US10124066B2 (en) 2012-11-29 2018-11-13 Insmed Incorporated Stabilized vancomycin formulations
US11571386B2 (en) 2018-03-30 2023-02-07 Insmed Incorporated Methods for continuous manufacture of liposomal drug products

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2012750B1 (en) * 2006-04-06 2018-02-21 Insmed Incorporated Methods for coacervation induced liposomal encapsulation and formulations thereof
US9333214B2 (en) 2007-05-07 2016-05-10 Insmed Incorporated Method for treating pulmonary disorders with liposomal amikacin formulations
JP2016524993A (ja) * 2013-07-17 2016-08-22 インスメッド， インコーポレイテッド 低抵抗エアロゾル呼気フィルタ
EP3129004A4 (en) 2014-04-08 2017-11-15 Aradigm Corporation Liposomal ciprofloxacin formulations with activity against non-tuberculous mycobacteria
CN104873463A (zh) * 2015-03-06 2015-09-02 朱孝云 用于治疗肺部感染的1-N-乙基庆大霉素Cla或其衍生物新制剂
CN107708875A (zh) * 2015-06-10 2018-02-16 斯坦福设备有限公司 气雾剂产生
US11285285B2 (en) 2016-05-03 2022-03-29 Pneuma Respiratory, Inc. Systems and methods comprising a droplet delivery device and a breathing assist device for therapeutic treatment
CN110799231B (zh) 2017-05-19 2022-08-02 精呼吸股份有限公司 干粉输送装置及其使用方法
JP7165146B2 (ja) * 2017-05-22 2022-11-02 インスメッド インコーポレイテッド グリコペプチド誘導体化合物およびそれらの使用
WO2019071008A1 (en) 2017-10-04 2019-04-11 Pneuma Respiratory, Inc. ELECTRONIC DEVICE FOR DELIVERY OF LINEAR SHAPE ADMINISTRATION OPERATED BY BREATHING AND METHODS OF USE
WO2019079461A1 (en) 2017-10-17 2019-04-25 Pneuma Respiratory, Inc. NASAL MEDICATION DELIVERY APPARATUS AND METHODS OF USE
CA3082192A1 (en) 2017-11-08 2019-05-16 Pneuma Respiratory, Inc. Electronic breath actuated in-line droplet delivery device with small volume ampoule and methods of use
US20190282565A1 (en) * 2018-03-19 2019-09-19 Gui-Bai Liang Methods and Compositions for Treating Idiopathic Pulmonary Fibrosis
US20210106772A1 (en) * 2018-04-02 2021-04-15 Pneuma Respiratory, Inc. Handheld digital nebulizer device and methods of use
EP3563894B1 (en) * 2018-05-04 2021-12-22 Boehringer Ingelheim International GmbH Nebulizer and container
EA202092892A1 (ru) 2018-12-04 2021-05-27 Брес Терапьютикс Гмбх Ингаляционные композиции, содержащие макроциклические иммуносупрессанты
WO2022204376A1 (en) * 2021-03-24 2022-09-29 Insmed Incorporated Combination therapy for treating non-tuberculous mycobacterial lung disease
US11793945B2 (en) 2021-06-22 2023-10-24 Pneuma Respiratory, Inc. Droplet delivery device with push ejection
KR102615869B1 (ko) * 2021-11-05 2023-12-21 연세대학교 산학협력단 마이코박테리움 아비움 복합체 폐질환 환자의 정보에 따른 치료 반응 예측용 지질대사체 마커
KR102596057B1 (ko) * 2021-11-05 2023-11-01 연세대학교 산학협력단 마이코박테리움 아비움 복합체 감염질환 진단용 지질대사체 마커
EP4249022A1 (en) * 2022-03-21 2023-09-27 PARI Pharma GmbH Drug-device combination

Family Cites Families (266)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3091572A (en) 1962-07-16 1963-05-28 Schering Corp Gentamycin and method of production
US3136704A (en) 1962-12-05 1964-06-09 Schering Corp Manufacture of gentamycin
US4394448A (en) 1978-02-24 1983-07-19 Szoka Jr Francis C Method of inserting DNA into living cells
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
GB2046092B (en) 1979-03-05 1983-11-02 Toyama Chemical Co Ltd Pharmaceutical composition containing a lysophospholid and a phospholipid
HU184141B (en) 1979-12-27 1984-07-30 Human Oltoanyagtermelo Adjuvant particles compositions containing said particles and biologically active substances adsorbed thereon and a process for the preparation thereof
US4451447A (en) 1980-03-31 1984-05-29 Bristol-Myers Company Pharmaceutical formulations
ATE18353T1 (de) 1981-07-02 1986-03-15 Hoffmann La Roche Verfahren zur herstellung von liposomenloesungen.
US4547490A (en) 1981-12-31 1985-10-15 Neomed, Inc. Synthetic whole blood and a method of making the same
US4522803A (en) 1983-02-04 1985-06-11 The Liposome Company, Inc. Stable plurilamellar vesicles, their preparation and use
US4684625A (en) 1982-07-08 1987-08-04 Syntex (U.S.A.) Inc. Method for enhancing the anti-infective activity of muramyldipeptide derivatives
US4981692A (en) 1983-03-24 1991-01-01 The Liposome Company, Inc. Therapeutic treatment by intramammary infusion
US4588578A (en) 1983-08-08 1986-05-13 The Liposome Company, Inc. Lipid vesicles prepared in a monophase
US5030453A (en) 1983-03-24 1991-07-09 The Liposome Company, Inc. Stable plurilamellar vesicles
US5169637A (en) 1983-03-24 1992-12-08 The Liposome Company, Inc. Stable plurilamellar vesicles
US4515736A (en) 1983-05-12 1985-05-07 The Regents Of The University Of California Method for encapsulating materials into liposomes
CA1237670A (en) 1983-05-26 1988-06-07 Andrew S. Janoff Drug preparations of reduced toxicity
US5059591B1 (en) 1983-05-26 2000-04-25 Liposome Co Inc Drug preparations of reduced toxicity
US4606939A (en) 1983-06-22 1986-08-19 The Ohio State University Research Foundation Small particle formation
CA1237671A (en) 1983-08-01 1988-06-07 Michael W. Fountain Enhancement of pharmaceutical activity
GB8322178D0 (en) 1983-08-17 1983-09-21 Sterwin Ag Preparing aerosol compositions
WO1985000968A1 (en) 1983-09-06 1985-03-14 Health Research, Inc. Liposome delivery method for decreasing the toxicity of an antitumor drug
US4721612A (en) 1984-04-12 1988-01-26 The Liposome Company, Inc. Steroidal liposomes
US4963367A (en) 1984-04-27 1990-10-16 Medaphore, Inc. Drug delivery compositions and methods
US4794000A (en) 1987-01-08 1988-12-27 Synthetic Blood Corporation Coacervate-based oral delivery system for medically useful compositions
US5008050A (en) 1984-06-20 1991-04-16 The Liposome Company, Inc. Extrusion technique for producing unilamellar vesicles
SE8403905D0 (sv) 1984-07-30 1984-07-30 Draco Ab Liposomes and steroid esters
US5077056A (en) 1984-08-08 1991-12-31 The Liposome Company, Inc. Encapsulation of antineoplastic agents in liposomes
US4880635B1 (en) 1984-08-08 1996-07-02 Liposome Company Dehydrated liposomes
US5736155A (en) 1984-08-08 1998-04-07 The Liposome Company, Inc. Encapsulation of antineoplastic agents in liposomes
WO1986006959A1 (en) 1985-05-22 1986-12-04 Liposome Technology, Inc. Liposome inhalation method and system
US5059421A (en) 1985-07-26 1991-10-22 The Liposome Company, Inc. Preparation of targeted liposome systems of a defined size distribution
US5409704A (en) 1985-06-26 1995-04-25 The Liposome Company, Inc. Liposomes comprising aminoglycoside phosphates and methods of production and use
US4975282A (en) 1985-06-26 1990-12-04 The Liposome Company, Inc. Multilamellar liposomes having improved trapping efficiencies
EP0231261B1 (en) 1985-07-05 1994-04-06 The Liposome Company, Inc. Multilamellar liposomes having improved trapping efficiencies
JPH0665648B2 (ja) 1985-09-25 1994-08-24 塩野義製薬株式会社 白金系抗癌物質の安定な凍結真空乾燥製剤
US4861580A (en) 1985-10-15 1989-08-29 The Liposome Company, Inc. Composition using salt form of organic acid derivative of alpha-tocopheral
US5041278A (en) 1985-10-15 1991-08-20 The Liposome Company, Inc. Alpha tocopherol-based vesicles
US5041581A (en) 1985-10-18 1991-08-20 The University Of Texas System Board Of Regents Hydrophobic cis-platinum complexes efficiently incorporated into liposomes
US5023087A (en) 1986-02-10 1991-06-11 Liposome Technology, Inc. Efficient method for preparation of prolonged release liposome-based drug delivery system
US4833134A (en) 1986-08-19 1989-05-23 Takeda Chemical Industries, Ltd. Cephem compounds
US5049388A (en) 1986-11-06 1991-09-17 Research Development Foundation Small particle aerosol liposome and liposome-drug combinations for medical use
US4933121A (en) 1986-12-10 1990-06-12 Ciba Corning Diagnostics Corp. Process for forming liposomes
US5320906A (en) 1986-12-15 1994-06-14 Vestar, Inc. Delivery vehicles with amphiphile-associated active ingredient
DE3785198T3 (de) 1986-12-23 1999-09-02 Liposome Co Inc Liposomes präparat und antibiotikum.
US5723147A (en) 1987-02-23 1998-03-03 Depotech Corporation Multivesicular liposomes having a biologically active substance encapsulated therein in the presence of a hydrochloride
US5616334A (en) 1987-03-05 1997-04-01 The Liposome Company, Inc. Low toxicity drug-lipid systems
MX9203808A (es) 1987-03-05 1992-07-01 Liposome Co Inc Formulaciones de alto contenido de medicamento: lipido, de agentes liposomicos-antineoplasticos.
US4857311A (en) 1987-07-31 1989-08-15 Massachusetts Institute Of Technology Polyanhydrides with improved hydrolytic degradation properties
US4895452A (en) 1988-03-03 1990-01-23 Micro-Pak, Inc. Method and apparatus for producing lipid vesicles
US5269979A (en) 1988-06-08 1993-12-14 Fountain Pharmaceuticals, Inc. Method for making solvent dilution microcarriers
IL91664A (en) 1988-09-28 1993-05-13 Yissum Res Dev Co Ammonium transmembrane gradient system for efficient loading of liposomes with amphipathic drugs and their controlled release
BE1001869A3 (fr) 1988-10-12 1990-04-03 Franz Legros Procede d'encapsulation liposomiale d'antibiotiques aminoglucosidiques, en particulier de la gentamycine.
US4952405A (en) 1988-10-20 1990-08-28 Liposome Technology, Inc. Method of treating M. avium infection
US4906476A (en) 1988-12-14 1990-03-06 Liposome Technology, Inc. Novel liposome composition for sustained release of steroidal drugs in lungs
US5006343A (en) 1988-12-29 1991-04-09 Benson Bradley J Pulmonary administration of pharmaceutically active substances
US5843473A (en) 1989-10-20 1998-12-01 Sequus Pharmaceuticals, Inc. Method of treatment of infected tissues
US5542935A (en) 1989-12-22 1996-08-06 Imarx Pharmaceutical Corp. Therapeutic delivery systems related applications
US5820848A (en) 1990-01-12 1998-10-13 The Liposome Company, Inc. Methods of preparing interdigitation-fusion liposomes and gels which encapsulate a bioactive agent
US5279833A (en) 1990-04-04 1994-01-18 Yale University Liposomal transfection of nucleic acids into animal cells
US5264618A (en) 1990-04-19 1993-11-23 Vical, Inc. Cationic lipids for intracellular delivery of biologically active molecules
AU7908791A (en) 1990-05-08 1991-11-27 Liposome Technology, Inc. Direct spray-dried drug/lipid powder composition
US5614216A (en) 1990-10-17 1997-03-25 The Liposome Company, Inc. Synthetic lung surfactant
IT1245761B (it) 1991-01-30 1994-10-14 Alfa Wassermann Spa Formulazioni farmaceutiche contenenti glicosaminoglicani assorbibili per via orale.
US6629646B1 (en) 1991-04-24 2003-10-07 Aerogen, Inc. Droplet ejector with oscillating tapered aperture
ATE155695T1 (de) 1991-11-07 1997-08-15 Ritzau Pari Werk Gmbh Paul Vernebler insbesondere zur anwendung in geräten für die inhalationstherapie
US5770563A (en) 1991-12-06 1998-06-23 The United States Of America As Represented By The Department Of Health And Human Services Heparin- and sulfatide binding peptides from the type I repeats of human thrombospondin and conjugates thereof
US5858784A (en) 1991-12-17 1999-01-12 The Regents Of The University Of California Expression of cloned genes in the lung by aerosol- and liposome-based delivery
CA2126101A1 (en) 1991-12-17 1993-06-24 Robert J. Debs Gene therapy for cystic fibrosis transmembrane conductance regulator activity (cftr)
US5756353A (en) 1991-12-17 1998-05-26 The Regents Of The University Of California Expression of cloned genes in the lung by aerosol-and liposome-based delivery
US5334761A (en) 1992-08-28 1994-08-02 Life Technologies, Inc. Cationic lipids
US5871710A (en) 1992-09-04 1999-02-16 The General Hospital Corporation Graft co-polymer adducts of platinum (II) compounds
WO1994012155A1 (en) 1992-12-02 1994-06-09 Vestar, Inc. Antibiotic formulation and process
US5958449A (en) 1992-12-02 1999-09-28 Nexstar Pharmaceuticals, Inc. Antibiotic formulation and use for bacterial infections
US5665383A (en) 1993-02-22 1997-09-09 Vivorx Pharmaceuticals, Inc. Methods for the preparation of immunostimulating agents for in vivo delivery
US5395619A (en) 1993-03-03 1995-03-07 Liposome Technology, Inc. Lipid-polymer conjugates and liposomes
ZA938381B (en) 1993-03-22 1994-06-13 Inland Steel Co Apparatus and method for magnetically confining molten metal using concentrating fins
KR100315213B1 (ko) 1993-04-02 2002-07-03 질레스피 카롤 리포좀생산방법
CA2120197A1 (en) 1993-04-02 1994-10-03 Kenji Endo Stable aqueous dispersions containing liposomes
US5759571A (en) 1993-05-11 1998-06-02 Nexstar Pharmaceuticals, Inc. Antibiotic formulation and use for drug resistant infections
PT707472E (pt) 1993-07-08 2001-07-31 Liposome Co Inc Processo para controlar a dimensao de lipossomas
US5766627A (en) 1993-11-16 1998-06-16 Depotech Multivescular liposomes with controlled release of encapsulated biologically active substances
JPH09506866A (ja) 1993-12-14 1997-07-08 ジョーンズ ホプキンス ユニバーシティー スクール オブ メディシン 医薬として活性のある物質の免疫療法のための放出制御
DK0663241T3 (da) 1993-12-17 1999-04-19 Pari Gmbh Forstøverdyse
WO1995024929A2 (en) 1994-03-15 1995-09-21 Brown University Research Foundation Polymeric gene delivery system
US5610198A (en) 1994-03-18 1997-03-11 The United States Of America As Represented By The Department Of Health And Human Services Anti-mycobacterial compositions and their use for the treatment of tuberculosis and related diseases
DE59409856D1 (de) 1994-05-19 2001-10-11 Pari Gmbh Vorrichtung zur Trocknung und Pufferung von Aerosolen
US5550109A (en) 1994-05-24 1996-08-27 Magainin Pharmaceuticals Inc. Inducible defensin peptide from mammalian epithelia
US5543152A (en) 1994-06-20 1996-08-06 Inex Pharmaceuticals Corporation Sphingosomes for enhanced drug delivery
US5741516A (en) 1994-06-20 1998-04-21 Inex Pharmaceuticals Corporation Sphingosomes for enhanced drug delivery
US5993850A (en) 1994-09-13 1999-11-30 Skyepharma Inc. Preparation of multivesicular liposomes for controlled release of encapsulated biologically active substances
US5753613A (en) 1994-09-30 1998-05-19 Inex Pharmaceuticals Corporation Compositions for the introduction of polyanionic materials into cells
US5508269A (en) 1994-10-19 1996-04-16 Pathogenesis Corporation Aminoglycoside formulation for aerosolization
US6000394A (en) 1994-10-26 1999-12-14 Paul Rizau Pari-Werk Gmbh Generation of an aerosol of an exact dose
SA95160463B1 (ar) 1994-12-22 2005-10-04 استرا أكتيبولاج مساحيق للاستنشاق
US5662929A (en) 1994-12-23 1997-09-02 Universite De Montreal Therapeutic liposomal formulation
US5972379A (en) 1995-02-14 1999-10-26 Sequus Pharmaceuticals, Inc. Liposome composition and method for administering a quinolone
US5800833A (en) 1995-02-27 1998-09-01 University Of British Columbia Method for loading lipid vesicles
US5855610A (en) 1995-05-19 1999-01-05 Children's Medical Center Corporation Engineering of strong, pliable tissues
DE19520622C2 (de) 1995-06-06 2003-05-15 Pari Gmbh Vorrichtung zum Vernebeln von Fluiden
US5643599A (en) 1995-06-07 1997-07-01 President And Fellows Of Harvard College Intracellular delivery of macromolecules
US6521211B1 (en) 1995-06-07 2003-02-18 Bristol-Myers Squibb Medical Imaging, Inc. Methods of imaging and treatment with targeted compositions
EP0830381A4 (en) 1995-06-09 2000-11-22 William N Drohan CHITINE HYDROGELS, PRODUCTION METHOD AND USE
US5942253A (en) 1995-10-12 1999-08-24 Immunex Corporation Prolonged release of GM-CSF
WO1997014740A1 (en) 1995-10-19 1997-04-24 Receptagen Corporation Discrete-length polyethylene glycols
DE19602628C2 (de) 1996-01-25 2000-06-29 Pari Gmbh Vernebler
GB9602969D0 (en) 1996-02-13 1996-04-10 The Technology Partnership Plc Liquid supply apparatus
US5840702A (en) 1996-03-22 1998-11-24 Uab Research Foundation Cystic fibrosis treatment
US5875776A (en) 1996-04-09 1999-03-02 Vivorx Pharmaceuticals, Inc. Dry powder inhaler
US6132765A (en) 1996-04-12 2000-10-17 Uroteq Inc. Drug delivery via therapeutic hydrogels
DE19616573C2 (de) 1996-04-25 1999-03-04 Pari Gmbh Verwendung unterkritischer Treibmittelmischungen und Aerosole für die Mikronisierung von Arzneimitteln mit Hilfe dichter Gase
JP2000510460A (ja) 1996-04-26 2000-08-15 マゲイニン・ファーマシューティカルズ・インコーポレーテッド スクアラミンを他の抗癌剤と併用する上皮性悪性腫瘍の治療
US6254854B1 (en) 1996-05-24 2001-07-03 The Penn Research Foundation Porous particles for deep lung delivery
US6503881B2 (en) 1996-08-21 2003-01-07 Micrologix Biotech Inc. Compositions and methods for treating infections using cationic peptides alone or in combination with antibiotics
AU714992B2 (en) 1996-08-23 2000-01-13 Alza Corporation Liposomes containing a cisplatin compound
US5837282A (en) 1996-10-30 1998-11-17 University Of British Columbia Ionophore-mediated liposome loading
AU741439B2 (en) 1996-12-30 2001-11-29 Battelle Memorial Institute Formulation and method for treating neoplasms by inhalation
US6451784B1 (en) 1996-12-30 2002-09-17 Battellepharma, Inc. Formulation and method for treating neoplasms by inhalation
US6458373B1 (en) 1997-01-07 2002-10-01 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
DE19713636A1 (de) 1997-04-02 1998-10-08 Pari Gmbh Atemzugsimulator
DE19734022C2 (de) 1997-08-06 2000-06-21 Pari Gmbh Inhalationstherapiegerät mit einem Ventil zur Begrenzung des Inspirationsflusses
US6106858A (en) 1997-09-08 2000-08-22 Skyepharma, Inc. Modulation of drug loading in multivescular liposomes
US6090407A (en) 1997-09-23 2000-07-18 Research Development Foundation Small particle liposome aerosols for delivery of anti-cancer drugs
BR9814615A (pt) 1997-10-22 2001-10-16 Jens Ponikau Métodos e materiais para o tratamento e prevenção de inflamação do tecido da mucosa
US6051251A (en) 1997-11-20 2000-04-18 Alza Corporation Liposome loading method using a boronic acid compound
AU1656799A (en) 1997-12-12 1999-07-05 Inex Pharmaceuticals Corp. Cationic drugs encapsulated in anionic liposomes
GB9827370D0 (en) 1998-01-16 1999-02-03 Pari Gmbh Mouthpiece for inhalation therapy units
US6468532B1 (en) 1998-01-22 2002-10-22 Genentech, Inc. Methods of treating inflammatory diseases with anti-IL-8 antibody fragment-polymer conjugates
DE29923848U1 (de) 1998-05-27 2001-04-12 Euro Celtique Sa Präparate zur Anwendung von entzündungshemmenden, insbesondere antiseptischen Wirkstoffen und/oder die Wundheilung fördernden Wirkstoffen in den oberen Atemwegen und/oder dem Ohr
US6200598B1 (en) 1998-06-18 2001-03-13 Duke University Temperature-sensitive liposomal formulation
DE19827228C2 (de) 1998-06-18 2000-07-13 Pari Gmbh Flüssigkeitszerstäubervorrichtung
US6509323B1 (en) 1998-07-01 2003-01-21 California Institute Of Technology Linear cyclodextrin copolymers
US6916490B1 (en) 1998-07-23 2005-07-12 UAB Research Center Controlled release of bioactive substances
AU754559B2 (en) 1998-08-12 2002-11-21 New York University Liposomal bupivacaine compositions prepared using an ammonium sulfate gradient
DE19846382C1 (de) 1998-10-08 2000-07-06 Pari Gmbh Zählwerk und seine Verwendung in Inhalatoren, Verneblern oder ähnlichen Dosieraerosolvorrichtungen
NZ511568A (en) 1998-11-12 2003-08-29 Frank G An inhalation system using lipids for the delivery of bioactive compounds
US6855296B1 (en) 1998-11-13 2005-02-15 Optime Therapeutics, Inc. Method and apparatus for liposome production
AU756196B2 (en) 1998-11-13 2003-01-09 Optime Therapeutics, Inc. Method and apparatus for liposome production
HUP0105226A3 (en) 1998-12-17 2003-03-28 Pathogenesis Corp Seattle Method for the treatment of severe chronic bronchitis (bronchiectasis) with an aerosolized antibiotic
US6211162B1 (en) 1998-12-30 2001-04-03 Oligos Etc. Inc. Pulmonary delivery of protonated/acidified nucleic acids
IL144756A0 (en) 1999-02-08 2002-06-30 Alza Corp Method for controlling liposome size
US6613352B2 (en) 1999-04-13 2003-09-02 Universite De Montreal Low-rigidity liposomal formulation
US7297344B1 (en) * 1999-05-27 2007-11-20 Euro-Celtique, S.A. Preparations for the promotion of wound healing in the upper respiratory tract and/or ear
JP2003503313A (ja) 1999-06-03 2003-01-28 ジェシー エル エス オウ 細胞増殖及び細胞死を変調する方法及び組成物
WO2001005374A1 (en) 1999-07-15 2001-01-25 Inex Pharmaceuticals Corp. Methods for preparation of lipid-encapsulated therapeutic agents
US6352996B1 (en) 1999-08-03 2002-03-05 The Stehlin Foundation For Cancer Research Liposomal prodrugs comprising derivatives of camptothecin and methods of treating cancer using these prodrugs
US6235177B1 (en) 1999-09-09 2001-05-22 Aerogen, Inc. Method for the construction of an aperture plate for dispensing liquid droplets
US6962151B1 (en) * 1999-11-05 2005-11-08 Pari GmbH Spezialisten für effektive Inhalation Inhalation nebulizer
US6511676B1 (en) 1999-11-05 2003-01-28 Teni Boulikas Therapy for human cancers using cisplatin and other drugs or genes encapsulated into liposomes
DE19953317C1 (de) 1999-11-05 2001-02-01 Pari Gmbh Inhalationsvernebler
JP4198850B2 (ja) 1999-11-29 2008-12-17 オムロンヘルスケア株式会社 液体噴霧装置
IL150027A0 (en) 1999-12-04 2002-12-01 Res Dev Foundation Carbon dioxide enhancement of inhalation therapy
DE10004465A1 (de) 2000-02-02 2001-08-16 Pari Gmbh Inhalationsvernebler
US7025988B2 (en) 2000-02-04 2006-04-11 Lipoxen Technologies Limited Liposomes
US8336545B2 (en) 2000-05-05 2012-12-25 Novartis Pharma Ag Methods and systems for operating an aerosol generator
US7100600B2 (en) 2001-03-20 2006-09-05 Aerogen, Inc. Fluid filled ampoules and methods for their use in aerosolizers
US6948491B2 (en) 2001-03-20 2005-09-27 Aerogen, Inc. Convertible fluid feed system with comformable reservoir and methods
US7600511B2 (en) 2001-11-01 2009-10-13 Novartis Pharma Ag Apparatus and methods for delivery of medicament to a respiratory system
MXPA02010884A (es) 2000-05-05 2003-03-27 Aerogen Ireland Ltd Aparato y metodo para el suministro de medicamentos al sistema respiratorio.
US7971588B2 (en) 2000-05-05 2011-07-05 Novartis Ag Methods and systems for operating an aerosol generator
EP1292314A2 (en) 2000-05-23 2003-03-19 The Trustees of Columbia University in the City of New York Method for treating respiratory disorders associated with pulmonary elastic fiber injury comprising the use of glycosaminoglycans
US6338859B1 (en) 2000-06-29 2002-01-15 Labopharm Inc. Polymeric micelle compositions
US6521736B2 (en) 2000-09-15 2003-02-18 University Of Massachusetts Amphiphilic polymeric materials
MXPA03003401A (es) 2000-10-16 2004-06-30 Neopharm Inc Formulacion liposomica de mitoxantrona.
US6497901B1 (en) 2000-11-02 2002-12-24 Royer Biomedical, Inc. Resorbable matrices for delivery of bioactive compounds
EP1203614A1 (de) 2000-11-03 2002-05-08 Polymun Scientific Immunbiologische Forschung GmbH Verfahren und Vorrichtung zur Herstellung von Lipidvesikeln
AU1999802A (en) 2000-12-01 2002-06-11 Lawrence Boni Preparation of large liposomes by infusion into peg
DE10102846B4 (de) 2001-01-23 2012-04-12 Pari Pharma Gmbh Aerosolgenerator
CA2437555A1 (en) 2001-02-01 2002-08-08 Yiyu Zou Stabilised polymeric aerosols for pulmonary gene delivery
DE10109897A1 (de) 2001-02-21 2002-11-07 Novosom Ag Fakultativ kationische Liposomen und Verwendung dieser
US6546927B2 (en) 2001-03-13 2003-04-15 Aerogen, Inc. Methods and apparatus for controlling piezoelectric vibration
JP2002318193A (ja) * 2001-04-24 2002-10-31 Canon Inc ネブライザ及び高周波誘導結合プラズマ発光分析装置
US6732944B2 (en) 2001-05-02 2004-05-11 Aerogen, Inc. Base isolated nebulizing device and methods
US6554201B2 (en) 2001-05-02 2003-04-29 Aerogen, Inc. Insert molded aerosol generator and methods
US20030060451A1 (en) 2001-05-29 2003-03-27 Rajneesh Taneja Enhancement of oral bioavailability of non-emulsified formulations of prodrug esters with lecithin
DE10126807C2 (de) 2001-06-01 2003-12-04 Pari Gmbh Inhalationstherapiegerät mit einem Ventil zur Begrenzung des Inspirationsflusses
DE10126808C1 (de) 2001-06-01 2002-08-14 Pari Gmbh Inhalationsmaske
EP1269993A1 (en) 2001-06-21 2003-01-02 Applied NanoSystems B.V. Delivery of small hydrophilic molecules packaged into lipid vesicles
US6991809B2 (en) 2001-06-23 2006-01-31 Lyotropic Therapeutics, Inc. Particles with improved solubilization capacity
US7063860B2 (en) 2001-08-13 2006-06-20 University Of Pittsburgh Application of lipid vehicles and use for drug delivery
EP1424889A4 (en) 2001-08-20 2008-04-02 Transave Inc PROCESS FOR TREATING LUNG CANCERS
EP1304130B1 (de) 2001-10-18 2004-06-23 PARI GmbH Spezialisten für effektive Inhalation Inhalationstherapievorrichtung
EP1304131B1 (de) 2001-10-18 2005-06-29 PARI GmbH Spezialisten für effektive Inhalation Inhalationstherapievorrichtung
US20030096774A1 (en) 2001-11-21 2003-05-22 Igor Gonda Compositions of nucleic acids and cationic aminoglycosides and methods of using and preparing the same
ATE508735T1 (de) 2001-12-19 2011-05-15 Novartis Ag Pulmonale verabreichung von aminoglykosiden
JP4761709B2 (ja) 2002-01-15 2011-08-31 エアロジェン，インコーポレイテッド エアロゾル発生器を作動するための方法およびシステム
WO2003059423A1 (en) 2002-01-15 2003-07-24 Aerogen, Inc. Systems and methods for clearing aerosols from the effective anatomic dead space
AU2003225689B2 (en) 2002-03-05 2009-03-26 Transave, Inc. Methods for entrapment of bioactive agent in a liposome or lipid complex
US20030205226A1 (en) 2002-05-02 2003-11-06 Pre Holding, Inc. Aerosol medication inhalation system
ES2572770T3 (es) 2002-05-20 2016-06-02 Novartis Ag Aparato para proporcionar pulverización para tratamiento médico y métodos
ATE485031T1 (de) 2002-06-28 2010-11-15 Protiva Biotherapeutics Inc Verfahren und vorrichtung zur herstellung von liposomen
JP2006502233A (ja) 2002-08-02 2006-01-19 トランセーブ，インク． 白金凝集物およびその製造方法
EP1386672B1 (en) 2002-08-02 2010-04-07 PARI Pharma GmbH Fluid droplet production apparatus
WO2004017944A1 (en) 2002-08-23 2004-03-04 Neopharm, Inc. Liposomal gemcitabine compositions for better drug delivery
DE10239321B3 (de) 2002-08-27 2004-04-08 Pari GmbH Spezialisten für effektive Inhalation Aerosoltherapievorrichtung
KR100489701B1 (ko) 2002-10-09 2005-05-16 주식회사 태평양 고농도의 트리터페노이드를 함유하는 미소화 리포좀 및 그제조방법
US7879351B2 (en) 2002-10-29 2011-02-01 Transave, Inc. High delivery rates for lipid based drug formulations, and methods of treatment thereof
US7718189B2 (en) 2002-10-29 2010-05-18 Transave, Inc. Sustained release of antiinfectives
PT1581236E (pt) 2002-10-29 2013-12-24 Insmed Inc Libertação prolongada de anti-infecciosos
DE10250625A1 (de) 2002-10-30 2004-05-19 Pari GmbH Spezialisten für effektive Inhalation Inhalationstherapievorrichtung
AU2003298738A1 (en) 2002-11-26 2004-06-18 Su-Ming Chiang Liposomal formulations
DE10257381B4 (de) 2002-12-09 2006-09-14 Pari GmbH Spezialisten für effektive Inhalation Inhalationstherapievorrichtung
US7968115B2 (en) 2004-03-05 2011-06-28 Board Of Regents, The University Of Texas System Liposomal curcumin for treatment of cancer
US6900184B2 (en) 2003-04-14 2005-05-31 Wyeth Holdings Corporation Compositions containing pipercillin and tazobactam useful for injection
DE10320143A1 (de) 2003-05-06 2004-12-16 Pari GmbH Spezialisten für effektive Inhalation Vernebleranschlussvorrichtung für Beatmungsgeräte oder dergleichen
DE10322505B4 (de) 2003-05-19 2009-11-05 Pari GmbH Spezialisten für effektive Inhalation Inhalationstherapiemaske und -vorrichtung für Tiere
EP1628637A2 (en) 2003-05-30 2006-03-01 Alza Corporation Method of pulmonary administration of an agent
US8616195B2 (en) 2003-07-18 2013-12-31 Novartis Ag Nebuliser for the production of aerosolized medication
GB2388581A (en) 2003-08-22 2003-11-19 Danisco Coated aqueous beads
DE10345950A1 (de) 2003-10-02 2005-05-19 Pari GmbH Spezialisten für effektive Inhalation Inhalationstherapievorrichtung mit Ventil
DE10347994A1 (de) 2003-10-15 2005-06-16 Pari GmbH Spezialisten für effektive Inhalation Wässrige Aerosol-Zubereitung
DE10348237A1 (de) 2003-10-16 2005-05-19 Pari GmbH Spezialisten für effektive Inhalation Inhalationstherapievorrichtung mit einem Düsenvernebler
US20050214224A1 (en) 2003-11-04 2005-09-29 Nektar Therapeutics Lipid formulations for spontaneous drug encapsulation
US7452524B2 (en) * 2004-01-27 2008-11-18 Gilead Sciences, Inc. Method for improvement of tolerance for therapeutically effective agents delivered by inhalation
US7556799B2 (en) 2004-03-30 2009-07-07 Relypsa, Inc. Ion binding polymers and uses thereof
DE102004016985B4 (de) 2004-04-07 2010-07-22 Pari Pharma Gmbh Aerosolerzeugungsvorrichtung und Inhalationsvorrichtung
JP4452799B2 (ja) 2004-07-14 2010-04-21 独立行政法人産業技術総合研究所 コアセルベートを活用したリポソームの製造方法
DE102005006372B4 (de) 2005-02-11 2007-11-29 Pari GmbH Spezialisten für effektive Inhalation Inhalationstherapievorrichtung und Verfahren zu deren Betrieb
DE102005006374B3 (de) 2005-02-11 2006-07-20 Pari GmbH Spezialisten für effektive Inhalation Aerosolerzeugungsvorrichtung und Inhalationstherapiegerät mit einer derartigen Vorrichtung
DE102005006375B4 (de) 2005-02-11 2007-10-11 Pari GmbH Spezialisten für effektive Inhalation Aerosolerzeugungsvorrichtung für Inhalationstherapiegeräte
US20060198940A1 (en) * 2005-03-04 2006-09-07 Mcmorrow David Method of producing particles utilizing a vibrating mesh nebulizer for coating a medical appliance, a system for producing particles, and a medical appliance
JP2006263054A (ja) 2005-03-23 2006-10-05 Konica Minolta Sensing Inc 呼吸器系疾患関連解析データの取得方法、オキシメータシステム及びその動作プログラム、オキシメータ並びに酸素補給システム
EP1712220A1 (en) 2005-04-15 2006-10-18 PARI GmbH Spezialisten für effektive Inhalation Pharmaceutical aerosol composition
US9108211B2 (en) 2005-05-25 2015-08-18 Nektar Therapeutics Vibration systems and methods
DE102005024779B4 (de) 2005-05-31 2008-02-21 Pari GmbH Spezialisten für effektive Inhalation Atemzuggesteuerte Inhalationstherapievorrichtung
DE102005029498B4 (de) 2005-06-24 2007-08-30 Pari GmbH Spezialisten für effektive Inhalation Inhalationstherapievorrichtung
USD656604S1 (en) 2005-06-28 2012-03-27 Pari Gmbh Part for inhalation therapy nebuliser
DE102005034403B3 (de) 2005-07-22 2007-02-22 Airbus Deutschland Gmbh Führungsmittel für eine Vorrichtung zur Herstellung von Faservorformlingen im TFP-Verfahren für Verbundbauteile
AU2006274413B2 (en) 2005-07-27 2013-01-10 Arbutus Biopharma Corporation Systems and methods for manufacturing liposomes
DE602006008637D1 (de) 2005-09-07 2009-10-01 Philips Intellectual Property System und verfahren zum induktiven messen der bioimpedanz eines leitfähigen gewebes
KR100705981B1 (ko) 2005-10-12 2007-04-10 주식회사 리제론 인간 성장호르몬을 포함하는 탈모방지 또는 발모촉진용조성물
DE102006051512A1 (de) 2005-12-06 2007-06-14 Pari GmbH Spezialisten für effektive Inhalation Pharmazeutische Medikamentenzusammensetzungen mit Cyclosporin
EP3067046B1 (en) 2005-12-08 2020-03-25 Insmed Incorporated Lipid-based compositions of antiinfectives for treating pulmonary infections
DE102006001113B3 (de) 2006-01-09 2007-06-28 Pari GmbH Spezialisten für effektive Inhalation Aerosoltherapievorrichtung
US8263645B2 (en) 2006-02-03 2012-09-11 Pari Pharma Gmbh Disodium cromoglycate compositions and methods for administering same
DE102006006183A1 (de) 2006-02-10 2007-08-16 Pari GmbH Spezialisten für effektive Inhalation Inhalationstherapievorrichtung für die Anwendung bei Frühgeborenen und Kleinkindern
US7958887B2 (en) 2006-03-10 2011-06-14 Aradigm Corporation Nozzle pore configuration for intrapulmonary delivery of aerosolized formulations
DE102006012174A1 (de) 2006-03-16 2007-09-20 Pari GmbH Spezialisten für effektive Inhalation Inhalationstherapiegerätekompressor
EP2012750B1 (en) 2006-04-06 2018-02-21 Insmed Incorporated Methods for coacervation induced liposomal encapsulation and formulations thereof
DE102006017002B3 (de) 2006-04-11 2007-01-11 Pari GmbH Spezialisten für effektive Inhalation Inhalationstherapievorrichtung mit mehrfachen Düsen
USD583928S1 (en) 2006-04-27 2008-12-30 Pari Pharama Gmbh Nebulizer
WO2008039989A2 (en) * 2006-09-28 2008-04-03 Transave, Inc. Formulations of dnase and methods of use thereof
US8071127B2 (en) 2006-10-24 2011-12-06 Aradigm Corporation Dual action, inhaled formulations providing both an immediate and sustained release profile
US8268347B1 (en) 2006-10-24 2012-09-18 Aradigm Corporation Dual action, inhaled formulations providing both an immediate and sustained release profile
US8119156B2 (en) 2006-10-24 2012-02-21 Aradigm Corporation Dual action, inhaled formulations providing both an immediate and sustained release profile
EP1927373B1 (en) 2006-11-30 2012-08-22 PARI Pharma GmbH Inhalation nebulizer
EP1980285B1 (de) 2007-04-11 2009-11-18 PARI GmbH Spezialisten für effektive Inhalation Aerosoltherapievorrichtung
US20100196455A1 (en) 2007-05-04 2010-08-05 Transave, Inc. Compositions of Multicationic Drugs for Reducing Interactions with Polyanionic Biomolecules and Methods of Use Thereof
WO2008137917A1 (en) * 2007-05-07 2008-11-13 Transave, Inc. Method of treating bacterial infections with antibacterial formulations
US9114081B2 (en) * 2007-05-07 2015-08-25 Insmed Incorporated Methods of treating pulmonary disorders with liposomal amikacin formulations
US9119783B2 (en) 2007-05-07 2015-09-01 Insmed Incorporated Method of treating pulmonary disorders with liposomal amikacin formulations
US9333214B2 (en) 2007-05-07 2016-05-10 Insmed Incorporated Method for treating pulmonary disorders with liposomal amikacin formulations
EP2030644A1 (en) 2007-08-31 2009-03-04 PARI Pharma GmbH Aerosols for sinunasal drug delivery
DE102007056462B4 (de) 2007-11-23 2011-10-27 Pari Pharma Gmbh Einwegampulle für eine Vorrichtung zur Erzeugung von Aerosolen
DE102008022987A1 (de) 2008-05-09 2009-11-12 Pari Pharma Gmbh Vernebler für Beatmungsmaschinen und Beatmungsmaschine mit einem solchen Vernebler
EP2358830B1 (en) 2008-12-18 2019-08-07 Hewlett-Packard Development Company, L.P. Pigmented ink-jet inks with gloss-enhancing polymers
EP2248517B1 (en) 2009-05-08 2014-03-26 PARI Pharma GmbH Concentrated mast cell stabilizing pharmaceutical formulations
DE102009026636B4 (de) 2009-06-02 2011-04-14 Pari Pharma Gmbh Verfahren zum Verschweißen einer Membran mit einem Träger bei der Herstellung eines Membranverneblers
PL2453864T3 (pl) 2009-07-17 2017-09-29 Nektar Therapeutics Systemy i sposoby do napędzania szczelnie zamkniętych nebulizatorów
JP5841052B2 (ja) 2009-07-17 2016-01-06 ウェルズ ファーゴ バンク ナショナル アソシエイション 負圧により付勢され、且つシールされた噴霧器システムおよび方法
CN102472648B (zh) 2009-07-22 2014-04-16 皇家飞利浦电子股份有限公司 具有低响应时间和高灵敏度的热流量传感器集成电路
CN103052392A (zh) 2010-07-12 2013-04-17 赛利亚医药公司 通过氨基糖苷气雾给药治疗肺部感染
EP2457609A1 (en) 2010-11-24 2012-05-30 PARI Pharma GmbH Aerosol generator
EP3777938B1 (en) * 2011-06-08 2023-08-02 PARI Pharma GmbH Aerosol generator
SI2852391T1 (sl) 2012-05-21 2022-04-29 Insmed Incorporated Sistemi za obravnavo pljučnih infekcij
US20160193148A1 (en) 2013-08-01 2016-07-07 University Of Georgia Research Foundation, Inc. Liposomal formulations for the treatment of bacterial infections

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9827317B2 (en) 2002-10-29 2017-11-28 Insmed Incorporated Sustained release of antiinfectives
US9511082B2 (en) 2005-12-08 2016-12-06 Insmed Incorporated Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof
US9549939B2 (en) 2005-12-08 2017-01-24 Insmed Incorporated Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof
US9549925B2 (en) 2005-12-08 2017-01-24 Insmed Incorporated Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof
US10328071B2 (en) 2005-12-08 2019-06-25 Insmed Incorporated Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof
US9402845B2 (en) 2005-12-08 2016-08-02 Insmed Incorporated Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof
US9925205B2 (en) 2007-05-04 2018-03-27 Insmed Incorporated Compositions of multicationic drugs for reducing interactions with polyanionic biomolecules and methods of use thereof
US10064882B2 (en) 2007-05-07 2018-09-04 Insmed Incorporated Methods of treating pulmonary disorders with liposomal amikacin formulations
US9737555B2 (en) 2007-05-07 2017-08-22 Insmed Incorporated Method of treating pulmonary disorders with liposomal amikacin formulations
US9724301B2 (en) 2007-05-07 2017-08-08 Insmed Incorporated Methods of treating pulmonary disorders with liposomal amikacin formulations
US9566234B2 (en) 2012-05-21 2017-02-14 Insmed Incorporated Systems for treating pulmonary infections
US10124066B2 (en) 2012-11-29 2018-11-13 Insmed Incorporated Stabilized vancomycin formulations
US10471149B2 (en) 2012-11-29 2019-11-12 Insmed Incorporated Stabilized vancomycin formulations
US10238675B2 (en) 2014-05-15 2019-03-26 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US10251900B2 (en) 2014-05-15 2019-04-09 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US9895385B2 (en) 2014-05-15 2018-02-20 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US10398719B2 (en) 2014-05-15 2019-09-03 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US10588918B2 (en) 2014-05-15 2020-03-17 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US10751355B2 (en) 2014-05-15 2020-08-25 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US10828314B2 (en) 2014-05-15 2020-11-10 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US11395830B2 (en) 2014-05-15 2022-07-26 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US11446318B2 (en) 2014-05-15 2022-09-20 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US11571386B2 (en) 2018-03-30 2023-02-07 Insmed Incorporated Methods for continuous manufacture of liposomal drug products

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