WO2019213398A1 - Methods for the manufacture of liposomal drug formulations - Google Patents

Methods for the manufacture of liposomal drug formulations Download PDF

Info

Publication number
WO2019213398A1
WO2019213398A1 PCT/US2019/030404 US2019030404W WO2019213398A1 WO 2019213398 A1 WO2019213398 A1 WO 2019213398A1 US 2019030404 W US2019030404 W US 2019030404W WO 2019213398 A1 WO2019213398 A1 WO 2019213398A1
Authority
WO
WIPO (PCT)
Prior art keywords
stream
aminoglycoside
lipid
flow rate
amikacin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2019/030404
Other languages
English (en)
French (fr)
Inventor
Robert Worsham
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Insmed Inc
Original Assignee
Insmed Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to AU2019262117A priority Critical patent/AU2019262117C1/en
Priority to JP2021510282A priority patent/JP7449275B2/ja
Priority to EP19797021.3A priority patent/EP3787602A4/en
Priority to CA3098573A priority patent/CA3098573A1/en
Priority to CN201980042856.6A priority patent/CN112584821A/zh
Priority to US17/052,070 priority patent/US20210113467A1/en
Application filed by Insmed Inc filed Critical Insmed Inc
Priority to KR1020207034487A priority patent/KR20210024451A/ko
Publication of WO2019213398A1 publication Critical patent/WO2019213398A1/en
Anticipated expiration legal-status Critical
Priority to JP2024031179A priority patent/JP2024075590A/ja
Priority to US18/825,766 priority patent/US12521345B1/en
Priority to US19/413,999 priority patent/US20260096989A1/en
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1277—Preparation processes; Proliposomes

Definitions

  • Liposomal drug formulations enable the ability to target and enhance the uptake of active agents at specific sites of disease.
  • Such formulations have been developed to treat various pulmonary disorders, including those caused by pulmonary infections, where their characteristics make them an ideal choice for the inhalation delivery of anti-infective agents.
  • amikacin has been packaged in liposomes, and has been studied in multiple clinical trials in adult patients for the treatment of refractory nontub erculous mycobacterial (NTM) lung disease cause by Mycobacterium avium complex (MAC).
  • NTM nontub erculous mycobacterial
  • MAC Mycobacterium avium complex
  • liposomes containing a relatively high amikacin to lipid ratio have been prepared at the bench scale, it is well-known that it is not a routine matter to scale up such processes to produce, at the commercial manufacturing scale, liposomal formulations where parameters such as drag concentration, amount of lipid in the formulation, lipid-to-drug ratio, captured volume, drug leakage, viscosity, and particle size are consistently maintained within specification for clinical and/or commercial use.
  • the present invention addresses the need for a repeatable large-scale process for preparing liposomes containing an aminoglycoside antibiotic such as amikacin, and having a high aminoglycoside-to-lipid weight ratio (and in turn, a low lipid-to-aminoglycoside weight ratio) and superior encapsulation efficiency.
  • the present invention provides a method for the large-scale manufacture of a liposomal aminoglycoside formulation comprising a lipid and an aminoglycoside (e.g., amikacin), with a high aminoglycoside loading relative to the lipid concentration (i.e., a high relative weight ratio of aminoglycoside-to-lipid).
  • the lipid-to-aminoglycoside (e.g., amikacin) weight ratio (also referred to as the“L/D weight ratio”) in the liposomal suspension prepared according to method of the present invention is less than 1 : 1 upon completion of the process, for example between about 0.5: 1 and about 0.9: 1.
  • the lipid-to- aminoglycoside weight ratio of the liposomal suspension prepared according to the method of the present invention is about 0.7: 1 (lipid : aminoglycoside) upon completion of the manufacturing process.
  • the present invention relates to a method for the large-scale manufacture of a liposomal drug formulation comprising a lipid and aminoglycoside (e.g., amikacin), wherein the aminoglycoside is contained within the liposome with a high encapsulation efficiency (e.g., an encapsulation efficiency of at least about 40% prior to washing to remove free aminoglycoside from the formulation).
  • aminoglycoside e.g., amikacin
  • the method comprises mixing a first stream comprising a lipid with a second stream comprising an aminoglycoside to form a combined lipid-aminoglycoside stream.
  • the combined lipid-aminoglycoside stream comprises liposomally encapsulated aminoglycoside, which in one embodiment, is formed at the intersection of the lipid stream and the aminoglycoside stream.
  • the lipid-aminoglycoside stream is mixed with an aqueous saline solution in a reaction vessel (see, e.g., Figure 1).
  • the aminoglycoside is present in an aqueous solution prior to the mixing step.
  • the lipid is present in an alcoholic solution, e.g., an ethanolic solution, prior to the mixing step.
  • the lipid comprises a phospholipid and cholesterol.
  • the relative flow rate ratio of the second stream comprising aminoglycoside to the first stream comprising a lipid is about 1.5: 1 (aminoglycoside stream : lipid stream) to about 2: 1 (aminoglycoside stream : lipid stream).
  • the lipid comprises dipalmitoyJphosphatidylcholine (DPPC) and cholesterol.
  • DPPC dipalmitoyJphosphatidylcholine
  • the aqueous saline solution is added to the reaction vessel via a third stream.
  • the third stream is added to the reaction vessel at the same time as the combined lipid-aminoglycoside stream. In another embodiment, the third stream is added to the reaction vessel prior to the addition of the combined lipid-aminoglycoside stream to the reaction vessel. In another embodiment, the aqueous saline solution is at about room temperature prior to entering the reaction vessel. In one embodiment, the aqueous saline solution is about 1.5% aqueous sodium chloride.
  • the present invention provides a method for the large-scale manufacture of a liposomal drug formulation comprising a lipid and aminoglycoside (e.g., amikacin), wherein the aminoglycoside is encapsulated within or comp!exed with the liposome, prior to a washing step, at an encapsulation efficiency of at least 40%.
  • the weight ratio of lipid-to-aminoglycoside in the liposomal aminoglycoside formulation is less than 1 : 1, for example between about 0.5: 1 and about 0.9: 1 (e.g., about 0.7: 1).
  • the aminoglycoside is amikacin.
  • the amikacin is present as amikacin sulfate.
  • a first stream comprising a lipid is mixed with a second stream comprising an aminoglycoside to form a combined lipid-aminoglycoside stream (e.g., a lipid- amikacin stream) comprising liposomal aminoglycoside.
  • a combined lipid-aminoglycoside stream e.g., a lipid- amikacin stream
  • the liposomal aminoglycoside formulation is formed at the intersection of the two streams, i.e , upon formation of the combined lipid-aminoglycoside stream.
  • the flow rate of the first stream comprising a lipid is from about 0.5 kg/min to about 1.5 kg/min and the flow rate of the second stream comprising aminoglycoside is from about 1 kg/min to about 2 kg/min.
  • the flow' rate of the first stream comprising a lipid is from about 3 kg/min to about 4 kg/min and the flow rate of the second stream comprising the aminoglycoside is from about 5 kg/min to about 7 kg/min.
  • the relative flow' rate ratio of the second stream comprising aminoglycoside to the first stream comprising a lipid is about 1 5: 1 (aminoglycoside stream flow' rate : lipid stream flow rate) to about 2: 1 (aminoglycoside stream flow' rate : lipid stream flow rate).
  • the lipid comprises dipalmitoylphosphatidyl choline (DPPC) and cholesterol.
  • DPPC dipalmitoylphosphatidyl choline
  • the method for the large-scale manufacture of a liposomal drug formulation comprises mixing a first stream comprising a lipid with a second stream comprising aminoglycoside to form a combined lipid-aminoglycoside stream, and adding the combined lipid- aminoglycoside stream to a vessel comprising an aqueous saline solution.
  • the aqueous saline solution in one embodiment, is added to the reaction vessel via a third stream (see, e.g.. Figure 1)
  • the flow rate of the first stream comprising a lipid is from about 0.5 kg/rnin to about 1.5 kg/rnin and the flow rate of the second stream comprising aminoglycoside is from about 1 kg/min to about 2 kg/min
  • the flow rate of the third stream is from about 0.5 L/min and about 2.0 L/min, for example, from about 1.0 L/min to about 2.0 L/min, e.g. from about 1.0 L/min to about 1 .5 L/min, including about 1.25 L/min.
  • the flow rate of the third stream is from about 3 L/min and about 6 L/min, for example, from about 4 L/min to about 6 L/min, e.g. from about 4.5 L/min to about 5.5 L/min, including about 5 L/min.
  • aminoglycoside is intended to include the aminoglycoside free base and any pharmaceutically acceptable salt thereof.
  • amikacin is intended to include amikacin free base and any pharmaceutically acceptable salt thereof (e.g., amikacin sulfate).
  • the method for the large-scale manufacture of a liposomal aminoglycoside (e.g. amikacin) formulation comprises mixing a first stream comprising a lipid comprising a phospholipid with a second stream comprising aminoglycoside (e.g. amikacin) to form a combined lipid-aminoglycoside stream.
  • the lipid-aminoglycoside stream is mixed with an aqueous saline solution in a reaction vessel.
  • the phospholipid is a phosphatidylcholine.
  • the phosphatidylcholine is DP PC.
  • the lipid comprises a phospholipid and a sterol.
  • the sterol is cholesterol.
  • the lipid comprises DPPC and cholesterol.
  • the method for the large-scale manufacture of a liposomal aminoglycoside formulation comprises mixing a first stream comprising a lipid with a second stream comprising aminoglycoside, wherein the first stream is mixed with the second stream to form a combined lipid-aminoglycoside stream.
  • the combined lipid-aminoglycoside stream comprises liposomal aminoglycoside.
  • the liposomal aminoglycoside in one embodiment, is formed upon mixing the first stream and second stream, e.g., at the intersection of the two streams.
  • the combined lipid-aminoglycoside stream is added to a reaction vessel and mixed with an aqueous saline solution.
  • the aminoglycoside stream and the lipid stream are each maintained at a temperature from about 30 °C to about 50 °C prior to mixing. In a further embodiment, the aminoglycoside and lipid streams are each maintained at a temperature of from about 35 °C to about 45 °C, for example from about 38 °C to about 42 °C prior to mixing. In one embodiment, the combined lipid-aminoglycoside stream is cooled upon entering the reaction vessel. In another embodiment, the combined lipid-aminoglycoside stream is cooled by the aqueous saline solution in the reaction vessel.
  • the reaction vessel is maintained at a temperature from about 25 °C and about 40 °C, e.g., from about 27 °C to about 35 °C. In another embodiment, the reaction vessel is maintained at a temperature of about 30 °C. In another embodiment, the reaction vessel is maintained at a temperature of about 33 °C.
  • a liposomal aminoglycoside formulation is manufactured on a large-scale according to a method provided herein.
  • the concentration of aminoglycoside (e.g. amikacin) present in the liposomal drug formulation so prepared is about 10 g/L or greater, for example from about 50 g/L to about lOOg/L, including about 60 g/L to about 80 g/L and about 65 g/L to about 75 g/L (e.g., about 20 g/L, about 30 g/L, 40 about g/L, about 50 g/L, about 60 g/L, about 70 g/L or about 80 g/L).
  • the concentration of lipid present in the liposomal drug formulation so prepared is from about 10 g/L to about 100 g/L, including about 20 g/L to about 80 g/L and about 40 g/L to about 60 g/L (e.g. about 50 g/L).
  • the L/D ratio of a liposomal drug formulation manufactured on a large-scale according to a method provided herein is less than 1 : 1 , for example between about 0.5: 1 and about 0.8: 1 (e.g. about 0.7: 1).
  • the liposomal drug formulation manufactured on a large-scale according to a method provided herein comprises liposome particles with a mean particle size (i.e. a mean diameter) of from about 200 nm to about 500 nm, for example from about 200 nm to about 400 nm (e.g. from about 250 nm to about 350 nm).
  • a mean particle size i.e. a mean diameter
  • FIGURES Figure 1 depicting one embodiment of the invention for preparing a liposomal aminoglycoside formulation.
  • Figure 2 shows the effect of relative lipid/amikacin flow rates on the resulting L/D ratio of various liposomal amikacin formulations.
  • the invention described herein relates to a method for manufacturing a liposomal aminoglycoside formulation on a large-scale.
  • the method comprises mixing a first stream comprising a lipid (also referred to herein as a“lipid stream”) with a second stream comprising an aminoglycoside such as amikacin (also referred to herein as a“drug stream”) to form a combined lipid-aminoglycoside stream, and the lipid-aminoglycoside stream is mixed with an aqueous saline solution in a reaction vessel.
  • the aqueous saline solution enters the reaction vessel via a third stream.
  • the mixing of the lipid and drug streams is effected such that a turbulent flow results when forming the combined lipid-aminoglycoside stream.
  • a turbulent flow is conveniently achieved using an appropriate T-shaped or Y-shaped infusion module for“in-line” mixing of the lipid and drug streams.
  • the term“large-scale” means the use of at least about 5 kg aminoglycoside base starting material in the drug stream (calculated to at least about 5 kg aminoglycoside base if a pharmaceutically acceptable salt is used). In one embodiment, about 5 kg to about 50 kg aminoglycoside base starting material is used, for example about 5 kg to about 35 kg aminoglycoside base starting material. In one embodiment, at least about 8 kg aminoglycoside base starting material is used. In another embodiment, at least about 30 kg aminoglycoside base starting material is used. In one embodiment, the aminoglycoside is amikacin (e.g. amikacin sulfate).
  • aminoglycoside used in the methods provided herein can be present as a pharmaceutically acceptable salt or as the free base.
  • the aminoglycoside is amikacin, e.g., amikacin sulfate.
  • 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 AC4437, amikacin, apramycin, arbekacin, astromicin, bekanamycin, boholmycin, brulamycin, capreomycin, dibekacin, dactimicin, etimicin, framycetin, gentamicin, HI 07, hygromycin, hygromycin B, inosamycin, K- 4619, isepamicin, KA-5685, kanamycin, neomycin, netilmicin, paromomycm, plazomicin, ribostamycin, sisomicm, rhodestreptomycin, sorbistin, spectinomycin, sporaricin, streptomycin, tobramycin, verdamicin, vertilmicin, or a combination thereof.
  • A“pharmaceutically acceptable salt” includes both acid and base addition salts.
  • a pharmaceutically acceptable addition salt refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid (HC1), hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane- 1,2-disulfonic acid, e
  • the pharmaceutically acceptable salt is HC1, TFA, lactate or acetate.
  • the pharmaceutically acceptable salt is a sulfate salt, e.g., amikacin sulfate.
  • “Liposomal aminoglycoside formulation” refers to a lipid-aminoglycoside formulation wherein the lipid is in the form of a liposome and the aminoglycoside is encapsulated by the liposome bilayer, or complexed with the liposome bilayer. Liposomes are completely closed lipid bilayer membranes containing an entrapped aqueous volume.
  • Liposomes may be unilamellar vesicles (possessing a single membrane bilayer) or multilaraei!ar 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.
  • the lipid-aminoglycoside formulation is manufactured via a method comprising a two-stream infusion process.
  • the method comprises mixing a first lipid stream with a second aminoglycoside stream in a T-shaped infusion module or Y-shaped infusion module.
  • the terms“T-shaped infusion module,” and“Y-shaped infusion module” as used herein, refer to a T-shaped or Y-shaped chamber in which two or more streams are combined, for example, in which a lipid stream and a drug stream are combined to form a single lipid- aminoglycoside stream . See, e.g., the diagram at Figure 1. It will be appreciated that the infusion module will have a bore size appropriate for the required rate of the lipid and drug streams used. Examples of suitable bore sizes include, but are not limited to, 3/16” and 3/8”.
  • the first stream comprises an alcoholic (e.g., ethanolic) lipid solution.
  • the second stream comprises an aqueous aminoglycoside solution (e.g., aqueous amikacin solution).
  • the first and second streams are mixed to form a combined lipid-aminoglycoside stream.
  • the first and second streams each enter the infusion module and the first and second streams are mixed in the infusion module.
  • the combined lipid- aminoglycoside stream exits the infusion module and subsequently enters the reaction vessel. See Figure 1.
  • the combined lipid-aminoglycoside stream is mixed with an aqueous saline solution in a reaction vessel, e.g., the same reaction vessel that the combined lipid- aminoglycoside stream enters after exiting the infusion module.
  • the aqueous saline solution comprises about 0.5-2% aqueous sodium chloride solution (e.g., about 1.5%).
  • the saline solution is added to the reaction vessel prior to the combined lipid- aminoglycoside stream.
  • the saline solution is added to the reaction vessel at or about the same time as the combined lipid-aminoglycoside stream.
  • the saline solution is added to the reaction vessel via a third stream.
  • the lipid-aminoglycoside formulation is manufactured via a method comprising a 3-stream infusion process.
  • the third stream is added to the reaction vessel separately from the combined lipid-aminoglycoside stream.
  • the combined lipid-aminoglycoside stream comprises liposomal aminoglycoside, (e.g. amikacin), wherein the encapsulation efficiency of the aminoglycoside within the liposomes (or comp!exed to the liposomes) is at least about 40%.
  • Encapsulation efficiency refers to the amount of aminoglycoside encapsulated or eomplexed with liposomes prior to a filtration step, e.g., tangential flow filtration of the liposomal aminoglycoside formulation to remove free aminoglycoside.
  • an encapsulation efficiency of between about 40% and about 70% can be achieved by mixing the lipid and aminoglycoside (e.g. amikacin) streams according to the method of this invention as herein described.
  • the aminoglycoside stream and the lipid stream are each maintained at a temperature from about 30 °C to about 50 °C prior to mixing the two streams.
  • the aminoglycoside and lipid streams are each maintained at a temperature of from about 35 °C to about 45 °C, for example from about 38 °C to about 42 °C prior to mixing.
  • the combination of the lipid and aminoglycoside solutions exhibits exothermal behavior.
  • the temperature of the combined lipid-aminoglycoside stream in one embodiment, is from about 40 °C to 55 °C.
  • the temperature of the combined lipid-aminoglycoside stream is from about 45 °C to about 50 °C.
  • the combined lipid-aminoglycoside stream is mixed with an aqueous saline solution in a reaction vessel, wherein the aqueous saline solution is maintained at room temperature prior to mixing with the combined lipid-aminoglycoside stream.
  • an aqueous saline solution is added to the reaction vessel via a third stream, wherein the third stream is maintained at room temperature prior to mixing with the combined lipid-aminoglycoside stream.
  • the combined lipid-aminoglycoside stream is cooled upon entering the reaction vessel.
  • the combined lipid-aminoglycoside stream is cooled by the aqueous saline solution in the reaction vessel. In another embodiment, the combined lipid- aminoglycoside stream is cooled upon entering the reaction vessel. In one embodiment, the reaction vessel is maintained at a temperature from about 25 °C and about 40 °C, e.g., from about 27 C 'C to about 35 °C. In another embodiment, the reaction vessel is maintained at a temperature of about 30 °C. In another embodiment, the reaction vessel is maintained at a temperature of about
  • the lipid component of the liposomal drug formulation manufactured by the method provided herein comprises electrically net neutral lipids, positively charged lipids, negatively charged lipids, or a combination thereof.
  • the lipid component comprises electrically net neutral lipids.
  • the lipid component consists essentially of electrically net neutral lipids.
  • the lipid is DPPC and cholesterol.
  • the lipids used in the manufacture of the liposomal formulations of the present invention can be synthetic, semi -synthetic or naturally-occurring lipids, including one or more of phospholipids, tocopherols, sterols, fatty acids, negatively-charged lipids and cationic lipids.
  • the lipid component consists of electrically neutral lipids, e.g., a sterol and a phospholipid.
  • the phospholipid is phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidic acid (PA), soy phosphatidylcholine (SPC), soy phosphatidylglycerol (SPG), soy phosphatidylserine (SPS), soy phosphatidylinositol (SPI), soy phosphatidylethanolamine (SPE), and soy phosphatidic acid (SPA); hydrogenated egg and soya counterparts (e.g., hydrogenated egg phosphatidylcholine and hydrogenated soy phosphatidylcholine), phospholipids made up of ester linkages of fatty acids in the 2 and 3 of glycerol (PG), phosphatidylinositol (PI), phosphatidylserine (
  • the lipid component of the liposom al drug formulation manufactured by the method provided herein comprises a phosphatidylcholine.
  • the lipid component in the liposomal drug formulation comprises dipalmitoy!phosphatidyicho!ine (DPPC).
  • the lipid component of the liposomal drug formulation comprises DPPC and a sterol, for example DPPC and cholesterol.
  • the lipid consists essentially of DPPC and cholesterol, or consists of DPPC and cholesterol.
  • the DPPC and cholesterol have a molar ratio in the range of from about 19: 1 (DPPC : cholesterol) to about 1 : 1 (DPPC : cholesterol), or from about 9: 1 (DPPC : cholesterol) to about 1 : 1(DPPC : cholesterol) , or from about 4: 1 (DPPC : cholesterol) to about 1 : 1 (DPPC : cholesterol), or from about 2: 1 (DPPC : cholesterol) to about 1 : 1 (DPPC : cholesterol).
  • the DPPC and cholesterol have a molar ratio of about 2: 1 (DPPC : cholesterol).
  • lipid components of the liposomal drug formulation manufactured by the method provided herein include, but are not limited to, dimyristoylphosphatklycholine (DMPC), dimyristoylphosphatidyJglycerol (DMPG), dipalmitoylphosphatidcholine (DPPC), dipa!mitoylphosphatidylglyceroi (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 dimyristoylphosphatklycholine
  • DPPC dipalmitoylphosphatidcholine
  • DPPG dipa!mitoylphosphatidylg
  • Examples of sterol compounds in the liposomal drug formulation manufactured by the method provided herein 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 tocopherol s.
  • the tocopherols include tocopherol s, esters of tocopherol s including tocopherol hemi-succinates, salts of tocopherols including tocopherol hydrogen sulfates and tocopherol sulfates.
  • the term “sterol compound” includes sterols, tocopherol s and the like. Tocopherols and their water-soluble derivatives have been used to form liposomes, see, e.g., PCX Publication No. 87/02219.
  • the concentration of lipid in the first stream is from about 10 g/L to about 50 g/L, or from about 10 g/L to about 30g/L, or from about 15 g/L to about 25 g/L. In one embodiment, the concentration of lipid in the first stream is about 17g/L, about 18 g/L, about 19 g/L, about 20 g/L, about 21 g/L, about 22 g/L, about 23 g/L, about 24 g/L or about 25 g/L. In one embodiment, the concentration of lipid in the first strea is about 20 g/L
  • the concentration of aminoglycoside in the second stream is from about 10 g/L to about 100 g/L; or from about 20 g/L to about 70 g/L, or from about 30 g/L, to about 60 g/L; or from about 40 g/L to about 50 g/L.
  • the concentration of drug in the second stream is about 4 ' g/L, about 42 g/L, about 43 g/L, about 44 g/L, about 45 g/L, about 46 g/L, about 47 g/L, about 48 g/L, about 49 g/L or about 50 g/L.
  • the concentration of aminoglycoside in the second stream is about 45 g/L.
  • the aminoglycoside is amikacin.
  • the pH of the aminoglycoside stream is from 6 to about 7, or from about 6.5 to about 7.0. In a further embodiment, the pH of the aminoglycoside stream is about 6.7.
  • the aminoglycoside stream pH may be adjusted to the appropriate pH using a suitable base, such as an alkali or alkaline earth metal hydroxide, e.g. sodium hydroxide.
  • the aqueous saline solution comprises about 0.5% sodium chloride to about 3% sodiu chloride, for example about 0.75%, about 1.0%, about 1.25%, about 1.5%, about 1.75%, about 2.0%, or about 2.5% sodium chloride. In one embodiment, the aqueous saline solution comprises about 1.5% sodium chloride.
  • the flow rate of the lipid stream is from about 0 5 kg/min to about 1.5 kg/min and the flow rate of the aminoglycoside stream is from about 1 kg/min to about 2 kg/min. In a further embodiment, the flow rate of the lipid stream is from about 3 kg/min to about 4 kg/min and the flow rate of the drug stream is from about 5 kg/min to about 7 kg/min. In another embodiment, the relative flow rate ratio of the aminoglycoside stream to the lipid stream is about 1.5: 1 (aminoglycoside stream flow rate: lipid stream flow rate) to about 2: 1 (aminoglycoside stream flow rate : lipid stream flow rate).
  • the flow rate of the third stream comprising aqueous saline solution is from about 0.5 L/min and about 2.0 L/min, for example, from about 1.0 L/min to about 2.0 L/min, e.g., from about 1.0 L/min to about 1.5 L/min, including about 1.25 L/rnin.
  • the flow rate of the third stream comprising the aqueous saline solution is from about 3 L/min and about 6 L/min, for example, from about 4 L/min to about 6 L/min, e.g. from about 4.5 L/min to about 5.5 L/min, including about 5 L/min.
  • the lipid and aminoglycoside (e.g., amikacin) solutions are both filtered, for example through one or more (e.g., two in series) about 0.2 pm filters, prior to mixing into a combined stream ( Figure 1).
  • Figure 1 shows two filters in series, it should be noted that this number can be changed according to the preference of the user of the method. For example, one to five filters can be used to initially filter the lipid stream and the aminoglycoside stream.
  • the aqueous saline solution (e.g., 1.5% saline solution) is also filtered, for example through one or more (e.g., two in series) about 0.2 pm filters, prior to mixing with the lipid-aminoglycoside combined stream in the reaction vessel.
  • the liposomal suspension comprising liposomes formed at the intersection of the lipid and aminoglycoside streams, and/or in the combined lipid-aminoglycoside stream, is concentrated within the reaction vessel using a recirculating filtration system such as diafiltration.
  • encapsulation efficiency refers to the amount of aminoglycoside encapsulated or complexed with liposomes prior to a filtration step, e.g., tangential flow filtration of the liposomal aminoglycoside formulation to remove free aminoglycoside.
  • an encapsulation efficiency of between about 40% and about 70% e.g., from about 45% to about 55%) can be achieved by mixing the lipid and aminoglycoside (e.g. amikacin) streams according to the method of this invention as herein described.
  • the resulting concentrated liposomal suspension is treated (i.e., “washed”’) with additional aqueous saline solution (e.g., filtered 1.5% saline solution) and subjected to further filtration using a recirculating filtration system such as diafiltration until the liposomal suspension contains an appropriate final aminoglycoside concentration and substantially all of the free aminoglycoside is removed.
  • additional aqueous saline solution e.g., filtered 1.5% saline solution
  • three or more washes e.g., 3, 4, 5 or 6 washes
  • the concentration of aminoglycoside present in the liposomal aminoglycoside formulation manufactured on a large-scale according to a method provided herein is about 10 g/L or greater.
  • aminoglycoside is present in the formulation at a concentration of about 20 g/L or greater.
  • aminoglycoside is present in the formulation at a concentration of about 30 g/L or greater.
  • aminoglycoside is present in the formulation at a concentration of about 40 g/L or greater.
  • aminoglycoside is present in the formulation at a concentration of about 50 g/L or greater.
  • aminoglycoside is present in the formulation at a concentration of about 60 g/L or greater. In a further embodiment, aminoglycoside is present in the formulation at a concentration of about 70 g/L or greater. In another embodiment, the aminoglycoside is present in the formulation at a concentration of from about 10 g/L to about 100 g/L. In a further embodiment, the aminoglycoside is amikacin. In one embodiment, the aminoglycoside is present in the formulation at a concentration of from about 50 g/L to about 100 g/L. In a further embodiment, the aminoglycoside is amikacin.
  • the aminoglycoside is present in the formulation at a concentration of from about 60 g/L to about 80 g/L. In a further embodiment, the aminoglycoside is amikacin. In yet another embodiment, the aminoglycoside is present in the formulation at a concentration from about 65 g/L to about 80 g/L. In a further embodiment, the aminoglycoside is amikacin. In yet another embodiment, the aminoglycoside is present in the formulation at a concentration from about 65 g/L to about 75 g/L. In a further embodiment, the aminoglycoside is amikacin. In another embodiment, amikacin is present in the formulation at a concentration of about 70 g/L. In a further embodiment, the aminoglycoside is amikacin.
  • the concentration of lipid present in the liposomal drug formulation manufactured on a large-scale according to a method provided herein is from about 10 g/L to about 100 g/L, including about 20 g/L to about 80 g/L and about 40 g/L to about 60 g/L (e.g., about 50 g/L).
  • the lipid-to-aminog!ycoside weight ratio in a liposomal drug formulation manufactured on a large-scale according to a method provided herein is less than 1 : 1, for example between about 0.5: 1 (lipid : aminoglycoside) and about 0.8: 1 (lipid : aminoglycoside) (e.g., about 0.5: 1 (lipid : aminoglycoside) or 0.6: 1 (lipid : aminoglycoside) or 0.7: 1 (lipid : aminoglycoside) or 0.8: 1 (lipid : aminoglycoside)).
  • the lipid-to- aminoglycoside weight ratio is about 0.7: 1 (lipid : aminoglycoside).
  • the liposomal aminoglycoside formulation manufactured on a large-scale according to a method provided herein comprises liposome particles with a mean particle size (i.e. a mean diameter) of from about 200 nm to about 500 nm, for example from about 200 nm to about 400 nm (e.g. from about 250 nm to about 350 nm).
  • the liposome diameter may be measured using commercially available light scattering technology, for example by quasi-elastic light scattering using a NicompTM 380 submicron particle sizer (Nicomp, Santa Barbara, California USA).
  • the manufacture of liposomal amikacin sulfate was conducted using an aseptic process that involves the preparation of three sterile solution streams, mixing the lipid and amikacin sulfate streams at appropriate flow rates via a T-connector infusion module, collecting the combined lipid- amikacin sulfate streams containing liposomes with encapsulated amikacin sulfate in a sterilized diafiltration (reaction) vessel, adding a stream of 1 .5% aqueous sodium chloride at an appropriate flow rate to the diafiltration vessel, followed by diafiltration (including washing) and concentration of the resulting liposomal dispersion to form the final product.
  • a) Solution Preparation Sufficient quantities of the following three solutions were prepared.
  • ® Amikacin sulfate solution Amikacin sulfate in water for injection (WFI), pH adjusted with sodium hydroxide to 6.6-6.8.
  • ® Lipid solution DPPC/cholesterol (2: 1 w/w) in ethanol.
  • This step functions to remove the ethanol from the bulk solution and to wash away any“unentrapped” or free amikacin sulfate.
  • Table 1 describes experiments (A) and (B), performed according to the general method of Example 1
  • A a 3/8” T-connector infusion module is used.
  • B a 3/16” T-connector infusion module is used.
  • Example 2 In additional experiments, generally following the process of Example 1 , the lipid and amikacin stream (flow) rates were varied, and the resulting concentrations of lipid and amikacin in the liposomal formulations were measured. The L/D ratio for each experiment was calculated and the results presented in Figure 2. The results provide guidance for an optimal relative lipid/amikacin flow rate to achieve a preferred L/D ratio.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Molecular Biology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
PCT/US2019/030404 2018-05-02 2019-05-02 Methods for the manufacture of liposomal drug formulations Ceased WO2019213398A1 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
KR1020207034487A KR20210024451A (ko) 2018-05-02 2019-05-02 리포솜 약물 제형을 제조하는 방법
JP2021510282A JP7449275B2 (ja) 2018-05-02 2019-05-02 リポソーム薬物製剤の製造方法
EP19797021.3A EP3787602A4 (en) 2018-05-02 2019-05-02 PROCESS FOR THE MANUFACTURE OF LIPOSOMAL DRUG FORMULATIONS
CA3098573A CA3098573A1 (en) 2018-05-02 2019-05-02 Methods for the manufacture of liposomal drug formulations
CN201980042856.6A CN112584821A (zh) 2018-05-02 2019-05-02 脂质体药物配制品的制造方法
AU2019262117A AU2019262117C1 (en) 2018-05-02 2019-05-02 Methods for the manufacture of liposomal drug formulations
US17/052,070 US20210113467A1 (en) 2018-05-02 2019-05-02 Methods for the manufacture of liposomal drug formulations
JP2024031179A JP2024075590A (ja) 2018-05-02 2024-03-01 リポソーム薬物製剤の製造方法
US18/825,766 US12521345B1 (en) 2018-05-02 2024-09-05 Large-scale manufacturing methods for aminoglycosides
US19/413,999 US20260096989A1 (en) 2018-05-02 2025-12-09 Large-scale manufacturing methods for aminoglycosides

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201862665564P 2018-05-02 2018-05-02
US62/665,564 2018-05-02

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US17/052,070 A-371-Of-International US20210113467A1 (en) 2018-05-02 2019-05-02 Methods for the manufacture of liposomal drug formulations
US18/825,766 Continuation US12521345B1 (en) 2018-05-02 2024-09-05 Large-scale manufacturing methods for aminoglycosides

Publications (1)

Publication Number Publication Date
WO2019213398A1 true WO2019213398A1 (en) 2019-11-07

Family

ID=68386909

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2019/030404 Ceased WO2019213398A1 (en) 2018-05-02 2019-05-02 Methods for the manufacture of liposomal drug formulations

Country Status (8)

Country Link
US (3) US20210113467A1 (https=)
EP (1) EP3787602A4 (https=)
JP (2) JP7449275B2 (https=)
KR (1) KR20210024451A (https=)
CN (1) CN112584821A (https=)
AU (1) AU2019262117C1 (https=)
CA (1) CA3098573A1 (https=)
WO (1) WO2019213398A1 (https=)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12521345B1 (en) 2018-05-02 2026-01-13 Insmed Incorporated Large-scale manufacturing methods for aminoglycosides

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SMT202000516T1 (it) 2014-05-15 2020-11-10 Insmed Inc Metodi per trattamento di infezioni micobatteriche polmonati non tubercolari
EP3773505B1 (en) 2018-03-30 2026-04-29 Insmed Incorporated Methods for continuous manufacture of liposomal drug products

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007117550A2 (en) * 2006-04-06 2007-10-18 Transave, Inc. Methods for coacervation induced liposomal encapsulation and formulations thereof
US8702219B2 (en) 2008-12-18 2014-04-22 Hewlett-Packard Development Company, L.P. Pigmented ink-jet inks with gloss-enhancing polymers
US20150314002A1 (en) * 2012-11-29 2015-11-05 Insmed Incorporated Stabilized vancomycin formulations

Family Cites Families (356)

* 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
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4394448A (en) 1978-02-24 1983-07-19 Szoka Jr Francis C Method of inserting DNA into living cells
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
EP0069307B1 (de) 1981-07-02 1986-03-05 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Verfahren zur Herstellung von Liposomenlösungen
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
US5169637A (en) 1983-03-24 1992-12-08 The Liposome Company, Inc. Stable plurilamellar vesicles
US5030453A (en) 1983-03-24 1991-07-09 The Liposome Company, Inc. Stable plurilamellar vesicles
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
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
EP0153955A1 (en) 1983-09-06 1985-09-11 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
US5736155A (en) 1984-08-08 1998-04-07 The Liposome Company, Inc. Encapsulation of antineoplastic agents in liposomes
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
DE3686025T2 (de) 1985-05-22 1993-01-07 Liposome Technology Inc Verfahren und system zum einatmen von liposomen.
US5409704A (en) 1985-06-26 1995-04-25 The Liposome Company, Inc. Liposomes comprising aminoglycoside phosphates and methods of production and use
US5059421A (en) 1985-07-26 1991-10-22 The Liposome Company, Inc. Preparation of targeted liposome systems of a defined size distribution
US4975282A (en) 1985-06-26 1990-12-04 The Liposome Company, Inc. Multilamellar liposomes having improved trapping efficiencies
DE3689769T2 (de) 1985-07-05 1994-07-21 Liposome Co Inc Multilamellare liposome mit verbesserter einschliessungswirkung.
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
US5041278A (en) 1985-10-15 1991-08-20 The Liposome Company, Inc. Alpha tocopherol-based vesicles
US4861580A (en) 1985-10-15 1989-08-29 The Liposome Company, Inc. Composition using salt form of organic acid derivative of alpha-tocopheral
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
US6759057B1 (en) 1986-06-12 2004-07-06 The Liposome Company, Inc. Methods and compositions using liposome-encapsulated non-steroidal anti-inflammatory drugs
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
IL97538A (en) 1986-12-23 1995-03-15 Liposome Co Inc Multilamellar liposomes containing nonphosphate guanindino aminoglycosides and their preparation.
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
MX9203808A (es) 1987-03-05 1992-07-01 Liposome Co Inc Formulaciones de alto contenido de medicamento: lipido, de agentes liposomicos-antineoplasticos.
US5616334A (en) 1987-03-05 1997-04-01 The Liposome Company, Inc. Low toxicity drug-lipid systems
DE3852037T2 (de) 1987-07-29 1995-03-23 Liposome Co Inc Verfahren zur trennung von teilchen nach grösse.
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
MX9203504A (es) 1988-04-20 1992-07-01 Liposome Co Inc Complejo agente: lipido activo de alta proporcion.
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
US5580575A (en) 1989-12-22 1996-12-03 Imarx Pharmaceutical Corp. Therapeutic drug delivery systems
WO1991009616A1 (en) 1989-12-22 1991-07-11 Yale University Quinolone antibiotics encapsulated in lipid vesicles
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
JPH05507090A (ja) 1990-05-08 1993-10-14 リポサーム　テクノロジー　インコーポレイテッド 直接噴霧乾燥された薬剤／脂質粉末組成物
US6623671B2 (en) 1990-10-05 2003-09-23 Royden M. Coe Liposome extrusion process
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.
AU651414B2 (en) 1991-02-14 1994-07-21 Baxter International Inc. Binding of recognizing substances to liposomes
US6629646B1 (en) 1991-04-24 2003-10-07 Aerogen, Inc. Droplet ejector with oscillating tapered aperture
DK0540775T3 (da) 1991-11-07 1997-08-25 Ritzau Pari Werk Gmbh Paul Forstøver især til anvendelse i apparater til inhalationsterapi
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
WO1993012240A1 (en) 1991-12-17 1993-06-24 The Regents Of The University Of California Gene therapy for cystic fibrosis transmembrane conductance regulator activity (cftr)
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
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
US6890555B1 (en) 1992-02-05 2005-05-10 Qlt, Inc. Liposome compositions of porphyrin photosensitizers
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
AU3244393A (en) 1992-12-02 1994-06-22 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
CA2120197A1 (en) 1993-04-02 1994-10-03 Kenji Endo Stable aqueous dispersions containing liposomes
AU676906B2 (en) 1993-04-02 1997-03-27 Transave, Inc. Method of producing liposomes
US5759571A (en) 1993-05-11 1998-06-02 Nexstar Pharmaceuticals, Inc. Antibiotic formulation and use for drug resistant infections
US5497763A (en) 1993-05-21 1996-03-12 Aradigm Corporation Disposable package for intrapulmonary delivery of aerosolized formulations
JPH06345663A (ja) 1993-06-08 1994-12-20 Sumitomo Pharmaceut Co Ltd バンコマイシン含有リポソーム製剤
DK0707472T3 (da) 1993-07-08 2001-04-17 Liposome Co Inc Fremgangsmåde til regulering af størrelsen af liposomer
CA2101241C (en) 1993-07-23 1998-12-22 Jonathan P. Wong Liposome-encapsulated ciprofloxacin
AU683957B2 (en) 1993-11-05 1997-11-27 Amgen, Inc. Liposome preparation and material encapsulation method
US5766627A (en) 1993-11-16 1998-06-16 Depotech Multivescular liposomes with controlled release of encapsulated biologically active substances
CA2178902A1 (en) 1993-12-14 1995-06-22 The Johns Hopkins University School Of Medicine Controlled release of pharmaceutically active substances for immunotherapy
EP0663241B1 (de) 1993-12-17 1998-07-15 PARI GmbH Spezialisten für effektive Inhalation Zerstäuberdüse
EP0804249A2 (en) 1994-03-15 1997-11-05 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
AR002009A1 (es) 1994-12-22 1998-01-07 Astra Ab Composicion farmaceutica, procedimiento para la manufactura de un polvo de proliposoma como el utilizado en dicha composicion, procedimiento para lamanufactura de dicha composicion, uso de dicha composicion farmaceutica en la manufactura de un medicamento y dispositivo inhalador de polvo seco.
US5662929A (en) 1994-12-23 1997-09-02 Universite De Montreal Therapeutic liposomal formulation
US5883074A (en) 1995-02-08 1999-03-16 Microcide Pharmaceuticals, Inc. Potentiators of antibacterial agents
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
EP0825852B1 (en) 1995-04-18 2004-07-07 Yissum Research Development Company Of The Hebrew University Of Jerusalem Liposome drug-loading method and composition
US5855610A (en) 1995-05-19 1999-01-05 Children's Medical Center Corporation Engineering of strong, pliable tissues
JPH11508231A (ja) 1995-05-26 1999-07-21 ソマティックス セラピー コーポレイション 安定な脂質／核酸複合体を含む送達ビヒクル
DE69620136T2 (de) 1995-06-06 2002-08-01 Bayer Ag Antibakterielle präparate für die ohren ohne irritierende, sensibilisierende und ototoxische wirkungen
DE19520622C2 (de) 1995-06-06 2003-05-15 Pari Gmbh Vorrichtung zum Vernebeln von Fluiden
US6521211B1 (en) 1995-06-07 2003-02-18 Bristol-Myers Squibb Medical Imaging, Inc. Methods of imaging and treatment with targeted compositions
US5643599A (en) 1995-06-07 1997-07-01 President And Fellows Of Harvard College Intracellular delivery of macromolecules
JPH11507697A (ja) 1995-06-09 1999-07-06 エヌ． ドロハン，ウィリアム キチンヒドロゲル、それらの製造方法及び利用
US5942253A (en) 1995-10-12 1999-08-24 Immunex Corporation Prolonged release of GM-CSF
EP0856026A1 (en) 1995-10-19 1998-08-05 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
EP0914094A4 (en) 1996-03-28 2000-03-01 Univ Illinois MATERIALS AND METHOD FOR PRODUCING IMPROVED LIPOSOMAL AGENTS
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
CA2174803C (en) 1996-04-23 2000-07-11 Jonathan P. Wong Use of liposome encapsulated ciprofloxacin as an immunotherapeutic drug
DE19616573C2 (de) 1996-04-25 1999-03-04 Pari Gmbh Verwendung unterkritischer Treibmittelmischungen und Aerosole für die Mikronisierung von Arzneimitteln mit Hilfe dichter Gase
ES2201296T3 (es) 1996-04-26 2004-03-16 Genaera Corporation Escualmina en combinacion con otros farmacos anticancerigenos para el tratamiento de tumores.
GB9609779D0 (en) 1996-05-10 1996-07-17 Univ Bruxelles Freeze dried liposome encapsulated amphiphilic drug compositions and a process for the preparation thereof
US6254854B1 (en) 1996-05-24 2001-07-03 The Penn Research Foundation Porous particles for deep lung delivery
US6770291B2 (en) 1996-08-30 2004-08-03 The United States Of America As Represented By The Department Of Health And Human Services Liposome complexes for increased systemic 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
CA2263455C (en) 1996-08-23 2002-10-29 Sequus Pharmaceuticals, Inc. Liposomes containing a cisplatin compound
TW520297B (en) 1996-10-11 2003-02-11 Sequus Pharm Inc Fusogenic liposome composition and method
US6056973A (en) 1996-10-11 2000-05-02 Sequus Pharmaceuticals, Inc. Therapeutic liposome composition and method of preparation
US5837282A (en) 1996-10-30 1998-11-17 University Of British Columbia Ionophore-mediated liposome loading
US6451784B1 (en) 1996-12-30 2002-09-17 Battellepharma, Inc. Formulation and method for treating neoplasms by inhalation
EP0954283B1 (en) 1996-12-30 2007-03-21 Battelle Memorial Institute Use of a non-encapsulated anticancer drug for the preparation of a formulation 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
US20020039594A1 (en) 1997-05-13 2002-04-04 Evan C. Unger Solid porous matrices and methods of making and using the same
JP4142149B2 (ja) 1997-07-10 2008-08-27 明治製菓株式会社 バンコマイシンの凍結乾燥製剤
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
CA2215716C (en) 1997-09-17 1999-12-07 Her Majesty The Queen, In Right Of Canada, As Represented By The Ministe R Of National Defence Aerosol delivery of liposome-encapsulated fluoroquinolone
US6090407A (en) 1997-09-23 2000-07-18 Research Development Foundation Small particle liposome aerosols for delivery of anti-cancer drugs
DE19746287A1 (de) 1997-10-20 1999-04-22 Hoechst Marion Roussel De Gmbh Substituierte Isochinolin-2-Carbonsäureamide, ihre Herstellung und ihre Verwendung als Arzneimittel
TR200001117T2 (tr) 1997-10-22 2000-09-21 Ponikau Jens Mukozal dokudaki enflomasyonu önlemek ve tedavi etmek için maddeler ve yöntemler.
EP1030652B1 (en) 1997-11-14 2012-04-25 Pacira Pharmaceuticals, Inc. Production of multivesicular liposomes
US6051251A (en) 1997-11-20 2000-04-18 Alza Corporation Liposome loading method using a boronic acid compound
WO1999030686A1 (en) 1997-12-12 1999-06-24 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
DE29923847U1 (de) 1998-05-27 2001-04-12 Euroceltique S.A., Luxemburg/Luxembourg Präparate zur Anwendung von entzündungshemmenden, insbesondere antiseptischen Wirkstoffen und/oder die Wundheilung fördernden Wirkstoffen in den unteren Atemwegen
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
CA2340118C (en) 1998-08-12 2009-01-13 Yissum Research Development Company Of The Hebrew University Of Jerusalem 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
DE69935154T2 (de) 1998-11-12 2007-10-25 Inc. Transave Inhalationssystem
WO2000029103A1 (en) 1998-11-13 2000-05-25 Optime Therapeutics, Inc. Method and apparatus for liposome production
US6855296B1 (en) 1998-11-13 2005-02-15 Optime Therapeutics, Inc. Method and apparatus for liposome production
PL348812A1 (en) 1998-12-17 2002-06-17 Pathogenesis Corp 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
CA2361551A1 (en) 1999-02-08 2000-08-10 Alza Corporation Method for controlling liposome size
AU4054900A (en) 1999-04-02 2000-10-23 Advanced Medicine East, Inc. Desleucyl glycopeptide antibiotics and methods of making same
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
AU780194B2 (en) 1999-06-24 2005-03-10 Kyowa Hakko Kirin Co., Ltd. Method of regulating leakage of drug encapsulated in liposomes
CA2378430A1 (en) 1999-07-15 2001-01-25 Inex Pharmaceuticals Corp. Methods and apparatus for preparation of lipid vesicles
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
US6174878B1 (en) 1999-08-31 2001-01-16 Alcon Laboratories, Inc. Topical use of kappa opioid agonists to treat otic pain
US6235177B1 (en) 1999-09-09 2001-05-22 Aerogen, Inc. Method for the construction of an aperture plate for dispensing liquid droplets
DE19953317C1 (de) 1999-11-05 2001-02-01 Pari Gmbh Inhalationsvernebler
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
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
KR100799089B1 (ko) 1999-12-04 2008-01-29 리서치 디벨럽먼트 파운데이션 에어로졸화된 약물의 침착 증진 조성물
DE10004465A1 (de) 2000-02-02 2001-08-16 Pari Gmbh Inhalationsvernebler
JP4786105B2 (ja) 2000-02-04 2011-10-05 リポクセン テクノロジーズ リミテッド リポソーム
US6761877B2 (en) 2000-02-18 2004-07-13 Biocrystal, Ltd. Functionalized encapsulated fluorescent nanocrystals
US8336545B2 (en) 2000-05-05 2012-12-25 Novartis Pharma Ag Methods and systems for operating an aerosol generator
US6948491B2 (en) 2001-03-20 2005-09-27 Aerogen, Inc. Convertible fluid feed system with comformable reservoir and methods
US7971588B2 (en) 2000-05-05 2011-07-05 Novartis 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
MXPA02010884A (es) 2000-05-05 2003-03-27 Aerogen Ireland Ltd Aparato y metodo para el suministro de medicamentos al sistema respiratorio.
US7600511B2 (en) 2001-11-01 2009-10-13 Novartis Pharma Ag Apparatus and methods for delivery of medicament to a respiratory system
JP2004513071A (ja) 2000-05-23 2004-04-30 ザ・トラスティーズ・オブ・コロンビア・ユニバーシティ・イン・ザ・シティ・オブ・ニューヨーク 肺の弾性繊維損傷に関連した呼吸器疾患の治療方法
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
HUP0303719A2 (hu) 2000-10-16 2004-03-01 Neopharm, Inc. Mitoxantron hatóanyag-tartalmú liposzómás gyógyszerkészítmények és eljárás az előállításukra
CN1116875C (zh) 2000-10-19 2003-08-06 南京振中生物工程有限公司 紫杉醇脂质组合物及其制备方法
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
EP1343476B1 (en) 2000-12-01 2008-05-28 Biomira Inc. Preparation of large liposomes by infusion into peg
DE10102846B4 (de) 2001-01-23 2012-04-12 Pari Pharma Gmbh Aerosolgenerator
WO2002060412A2 (en) 2001-02-01 2002-08-08 Board Of Regents 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
US6554201B2 (en) 2001-05-02 2003-04-29 Aerogen, Inc. Insert molded aerosol generator and methods
US6732944B2 (en) 2001-05-02 2004-05-11 Aerogen, Inc. Base isolated nebulizing device and methods
PT1320355E (pt) 2001-05-18 2006-08-31 Chiron Corp Sistema para administracao de uma formulacao de tobramicina
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
JP2005502653A (ja) 2001-08-20 2005-01-27 トランセーヴ・インコーポレーテッド 肺ガンの治療方法
EP1418924A2 (en) 2001-08-21 2004-05-19 Pfizer Products Inc. Single dose azithromycin for treating respiratory infections
US6623723B2 (en) 2001-08-21 2003-09-23 Cellular Sciences Inc. Method for treating bronchial constriction and bronchospasm
ATE298600T1 (de) 2001-10-18 2005-07-15 Pari Gmbh Inhalationstherapievorrichtung
EP1304130B1 (de) 2001-10-18 2004-06-23 PARI GmbH Spezialisten für effektive Inhalation Inhalationstherapievorrichtung
CN1608133A (zh) 2001-10-26 2005-04-20 里伯药品公司 双链核糖核酸用于治疗正(+)链rna病毒感染的用途
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
JP2005514393A (ja) 2001-12-19 2005-05-19 ネクター セラピューティクス アミノグリコシドの肺への供給
ES2562682T3 (es) 2002-01-15 2016-03-07 Novartis Ag Sistema para liberar aerosoles del espacio muerto anatómico efectivo
EP1474196B1 (en) 2002-01-15 2016-08-17 Novartis AG Methods and systems for operating an aerosol generator
WO2003075889A1 (en) 2002-03-05 2003-09-18 Transave, Inc. An inhalation system for prevention and treatment of intracellular infections
US20030205226A1 (en) 2002-05-02 2003-11-06 Pre Holding, Inc. Aerosol medication inhalation system
AU2003256253A1 (en) 2002-05-20 2003-12-02 Aerogen, Inc. Aerosol for medical treatment and methods
US7901708B2 (en) 2002-06-28 2011-03-08 Protiva Biotherapeutics, Inc. Liposomal apparatus and manufacturing methods
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
AU2003268087A1 (en) 2002-08-23 2004-03-11 Ian Ma 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
US7718189B2 (en) 2002-10-29 2010-05-18 Transave, Inc. Sustained release of antiinfectives
US7879351B2 (en) 2002-10-29 2011-02-01 Transave, Inc. High delivery rates for lipid based drug formulations, and methods of treatment thereof
EP1581236B1 (en) 2002-10-29 2013-10-16 Insmed Incorporated Sustained release of antiinfectives
US20230008563A1 (en) 2002-10-29 2023-01-12 Insmed Incorporated Sustained release of antiinfectives
DE10250625A1 (de) 2002-10-30 2004-05-19 Pari GmbH Spezialisten für effektive Inhalation Inhalationstherapievorrichtung
JP4874547B2 (ja) 2002-11-26 2012-02-15 ギリアード サイエンシーズ， インコーポレイテッド 勾配によるリポソームへの薬物充填方法
US6861751B2 (en) * 2002-12-09 2005-03-01 Integrated Device Technology, Inc. Etch stop layer for use in a self-aligned contact etch
DE10257381B4 (de) 2002-12-09 2006-09-14 Pari GmbH Spezialisten für effektive Inhalation Inhalationstherapievorrichtung
EA200501285A1 (ru) 2003-02-11 2006-02-24 Неофарм, Инк. Способ получения липосомальных препаратов
CA2516836A1 (en) 2003-02-24 2004-09-10 Gtc Biotherapeutics, Inc. Methods of tangential flow filtration and an apparatus therefore
US7968115B2 (en) 2004-03-05 2011-06-28 Board Of Regents, The University Of Texas System Liposomal curcumin for treatment of cancer
HRP20150037T4 (hr) 2003-04-08 2022-09-02 Progenics Pharmaceuticals, Inc. Farmaceutske formulacije koje sadrže metilnaltrekson
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
US8058493B2 (en) 2003-05-21 2011-11-15 Baker Hughes Incorporated Removing amines from hydrocarbon streams
KR20060015265A (ko) 2003-05-30 2006-02-16 알자 코포레이션 제제의 폐 투여 방법
US8616195B2 (en) 2003-07-18 2013-12-31 Novartis Ag Nebuliser for the production of aerosolized medication
EP1666606A4 (en) 2003-08-20 2006-11-29 Locomogene Inc METHODS FOR IDENTIFYING REGULATORY EFFECTS ON THE ACTIVITY OF SYNOVIOLIN
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
WO2005044226A2 (en) 2003-11-04 2005-05-19 Nectar Therapeutics Lipid formulations for spontaneous drug encapsulation
PL1559431T3 (pl) 2003-12-31 2007-10-31 Orthologic Corp Kompozycja farmaceutyczna dla pochodnych peptydu trombiny
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
AU2005302255A1 (en) 2004-10-28 2006-05-11 Alza Corporation Lyophilized liposome formulations and method
CA2587411A1 (en) 2004-11-17 2006-05-26 Protiva Biotherapeutics, Inc. Sirna silencing of apolipoprotein b
US8337815B2 (en) 2004-12-23 2012-12-25 Discovery Laboratories, Inc. Pulmonary surfactant formulations
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
DE102005006372B4 (de) 2005-02-11 2007-11-29 Pari GmbH Spezialisten für effektive Inhalation Inhalationstherapievorrichtung und Verfahren zu deren Betrieb
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
BRPI0611198B1 (pt) 2005-05-25 2018-02-06 Aerogen, Inc. 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
US9005654B2 (en) 2005-07-27 2015-04-14 Protiva Biotherapeutics, Inc. Systems and methods for manufacturing liposomes
CN101253044B (zh) 2005-08-31 2011-11-23 东丽株式会社 聚乳酸类树脂叠层片和其成型体
US20080246472A1 (en) 2005-09-07 2008-10-09 Koninklijke Philips Electronics, N.V. System and Method for Inductively Measuring the Bio-Impedance of a Conductive Tissue
US20070065367A1 (en) 2005-09-20 2007-03-22 Rany Condos Method of treating pulmonary disease with interferons
KR100705981B1 (ko) 2005-10-12 2007-04-10 주식회사 리제론 인간 성장호르몬을 포함하는 탈모방지 또는 발모촉진용조성물
US20070105757A1 (en) 2005-10-31 2007-05-10 May Thomas B Vancomycin formulations having reduced amount of histamine
DE102006051512A1 (de) 2005-12-06 2007-06-14 Pari GmbH Spezialisten für effektive Inhalation Pharmazeutische Medikamentenzusammensetzungen mit Cyclosporin
HUE029994T2 (en) 2005-12-08 2017-04-28 Insmed Inc 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
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
US8119156B2 (en) 2006-10-24 2012-02-21 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
US8071127B2 (en) 2006-10-24 2011-12-06 Aradigm Corporation Dual action, inhaled formulations providing both an immediate and sustained release profile
US20080108104A1 (en) 2006-11-02 2008-05-08 Colorado State University Research Foundation Identification of bacterial species and subspecies using lipids
EP1927373B1 (en) 2006-11-30 2012-08-22 PARI Pharma GmbH Inhalation nebulizer
CA2678258A1 (en) 2007-02-09 2008-08-14 United Therapeutics Corporation Treprostinil treatment for interstitial lung disease and asthma
DE502007002037D1 (de) 2007-04-11 2009-12-31 Pari Gmbh Aerosoltherapievorrichtung
WO2008137717A1 (en) 2007-05-04 2008-11-13 Transave, Inc. Compositions of multicationic drugs for reducing interactions with polyanionic biomolecules and methods and uses thereof
US9114081B2 (en) 2007-05-07 2015-08-25 Insmed Incorporated Methods 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
US9119783B2 (en) 2007-05-07 2015-09-01 Insmed Incorporated Method of treating pulmonary disorders with liposomal amikacin formulations
WO2008137917A1 (en) 2007-05-07 2008-11-13 Transave, Inc. Method of treating bacterial infections with antibacterial formulations
UA27298U (en) 2007-06-13 2007-10-25 Method for preventing pleural empyema after pneumonectomy
UA27804U (en) 2007-07-26 2007-11-12 Method for preventing respiratory complications after surgery in lungs and pleura
EP2030644A1 (en) 2007-08-31 2009-03-04 PARI Pharma GmbH Aerosols for sinunasal drug delivery
NZ562236A (en) 2007-10-05 2010-04-30 Univ Otago Detection of volatile compounds as markers for Mycobacteria tuberculosis
CN103860469A (zh) 2007-10-23 2014-06-18 英斯麦德公司 脂质体万古霉素制剂
DE102007056462B4 (de) 2007-11-23 2011-10-27 Pari Pharma Gmbh Einwegampulle für eine Vorrichtung zur Erzeugung von Aerosolen
US10201587B2 (en) 2008-04-08 2019-02-12 Melinta Therapeutics, Inc. Methods of inhibiting and treating biofilms using glycopeptide antibiotics
DE102008022987A1 (de) 2008-05-09 2009-11-12 Pari Pharma Gmbh Vernebler für Beatmungsmaschinen und Beatmungsmaschine mit einem solchen Vernebler
CN104119242B (zh) 2008-10-09 2017-07-07 泰米拉制药公司 改善的氨基脂质和递送核酸的方法
US20120058198A1 (en) 2009-03-26 2012-03-08 Pulmatrix, Inc. Methods for treating and preventing pneumonia and ventilator-associated tracheobronchitis
ES2457442T3 (es) 2009-05-08 2014-04-25 Pari Pharma Gmbh Formulaciones farmacéuticas concentradas estabilizadoras de los mastocitos
DE102009026636B4 (de) 2009-06-02 2011-04-14 Pari Pharma Gmbh Verfahren zum Verschweißen einer Membran mit einem Träger bei der Herstellung eines Membranverneblers
KR101740624B1 (ko) 2009-07-17 2017-05-26 넥타르 테라퓨틱스 네거티브하게 바이어싱된 밀봉된 분무기 시스템들 및 방법들
WO2011009133A1 (en) 2009-07-17 2011-01-20 Nektar Therapeutics Systems and methods for driving sealed nebulizers
JP5580415B2 (ja) 2009-07-22 2014-08-27 コーニンクレッカ フィリップス エヌ ヴェ 短レスポンス時間及び高感度を持つ熱流センサ集積回路
WO2011038901A1 (en) 2009-09-29 2011-04-07 Activaero Gmbh Improved method for treatment of patients with cystic fibrosis
WO2011049960A2 (en) 2009-10-21 2011-04-28 Otonomy, Inc. Compositions and methods for the treatment of sinonasal disorders
US8536220B2 (en) 2010-01-26 2013-09-17 Murray Fulgham Supplement composition and method of use
WO2011108955A1 (en) 2010-03-03 2011-09-09 Universidade De Coimbra Multi -targeting system comprising a nanocarrier, nucleic acid(s) and non-nucleic acid based drug(s)
WO2011133617A1 (en) 2010-04-23 2011-10-27 The Board Of Trustees Of The University Of Illinois Nano-hybrid delivery system for sequential utilization of passive and active targeting
CA2801066C (en) 2010-06-02 2021-02-09 Alnylam Pharmaceuticals, Inc. Compositions and methods directed to treating liver fibrosis
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
CN103179951B (zh) 2010-08-20 2016-01-20 雷迪博士实验室有限公司 磷脂储库
CA2812952A1 (en) 2010-09-27 2012-04-12 Microdose Therapeutx, Inc. Methods and compositions for disease treatment using inhalation
EP3470057B1 (en) 2010-09-29 2021-11-03 Pulmatrix Operating Company, Inc. Cationic dry powders comprising magnesium salt
EP2457609A1 (en) 2010-11-24 2012-05-30 PARI Pharma GmbH Aerosol generator
JP6021117B2 (ja) 2011-01-31 2016-11-02 ジェノア ファーマシューティカルズ，インク． エアロゾルのピルフェニドンおよびピリドンアナログの化合物、および、その使用
EP2709646A4 (en) 2011-05-19 2015-05-13 Savara Inc DRY POWDER VANCOMYCIN COMPOSITIONS AND RELATED METHODS
EP3777938B1 (en) 2011-06-08 2023-08-02 PARI Pharma GmbH Aerosol generator
JP6294229B2 (ja) 2011-10-18 2018-03-14 ダイセルナ ファーマシューティカルズ， インコーポレイテッドＤｉｃｅｒｎａ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． アミン陽イオン性脂質およびその使用
US20140308304A1 (en) 2011-12-07 2014-10-16 Alnylam Pharmaceuticals, Inc. Lipids for the delivery of active agents
US20130177629A1 (en) 2011-12-22 2013-07-11 Nuvo Research Gmbh Liposomal compositions
US20130280174A1 (en) 2012-04-20 2013-10-24 The Gillette Company Personal care composition comprising metathesized unsaturated polyol esters
MX369828B (es) 2012-05-21 2019-11-22 Insmed Inc Sistemas para tratar infecciones pulmonares.
JP2015525799A (ja) 2012-08-10 2015-09-07 ユニバーシティ・オブ・ノース・テキサス・ヘルス・サイエンス・センターＵｎｉｖｅｒｓｉｔｙ ｏｆ Ｎｏｒｔｈ Ｔｅｘａｓ Ｈｅａｌｔｈ Ｓｃｉｅｎｃｅ Ｃｅｎｔｅｒ ターゲティングポリアミノ酸および脂肪酸のコンジュゲートを含む薬物送達ビークル
CA2925687A1 (en) 2012-09-27 2014-04-03 The University Of North Carolina At Chapel Hill Lipid coated nanoparticles containing agents having low aqueous and lipid solubilities and methods thereof
US9693958B2 (en) * 2013-03-15 2017-07-04 Cureport, Inc. Methods and devices for preparation of lipid nanoparticles
WO2015017807A1 (en) 2013-08-01 2015-02-05 University Of Georgia Research Foundation, Inc. Liposomal formulations for the treatment of bacterial infections
US9987227B2 (en) 2013-10-22 2018-06-05 Aradigm Corporation Inhaled surfactant-modified liposomal formulations providing both an immediate and sustained release profile
US20160120806A1 (en) 2014-04-08 2016-05-05 Aradigm Corporation Nanocrystals formed in a microenvironment
US9968555B2 (en) 2014-04-08 2018-05-15 Aradigm Corporation Liposomal formulations that form drug nanocrystals after freeze-thaw
EP3129004A4 (en) 2014-04-08 2017-11-15 Aradigm Corporation Liposomal ciprofloxacin formulations with activity against non-tuberculous mycobacteria
SMT202000516T1 (it) 2014-05-15 2020-11-10 Insmed Inc Metodi per trattamento di infezioni micobatteriche polmonati non tubercolari
KR102079585B1 (ko) 2014-08-29 2020-02-21 이엠디 밀리포어 코포레이션 잔류물의 재순환을 이용한 싱글 패스 접선 유동 여과 시스템 및 접선 유동 여과 시스템
CN107427791B (zh) 2015-03-19 2021-05-14 康涅狄格大学 用于连续制造脂质体药物制剂的系统和方法
EP3319976B1 (en) 2015-07-09 2021-09-01 Insmed Incorporated Compositions and methods for treating lung diseases and lung injury
JP2019500318A (ja) 2015-11-18 2019-01-10 インスメッド インコーポレイテッド 細菌感染症を治療するための組成物及び方法
GB201600290D0 (en) 2016-01-07 2016-02-24 Fujifilm Diosynth Biotechnologies Uk Ltd Process
US10183108B2 (en) 2016-02-04 2019-01-22 Pall Corporation Inline diafiltration with multi-channel pump
US20190029970A1 (en) 2017-07-31 2019-01-31 The Chinese University Of Hong Kong Fatty acid conjugated nanoparticles and uses thereof
EP3773505B1 (en) 2018-03-30 2026-04-29 Insmed Incorporated Methods for continuous manufacture of liposomal drug products
WO2019213398A1 (en) 2018-05-02 2019-11-07 Insmed Incorporated Methods for the manufacture of liposomal drug formulations
WO2020247912A1 (en) 2019-06-06 2020-12-10 Board Of Regents, The University Of Texas System Lipid nanoparticles containing pharmaceutical and/or nutraceutical agents and methods thereof
JP2024520789A (ja) 2021-06-09 2024-05-24 インスメッド インコーポレイテッド リポソームアミノグリコシド製剤のインビトロ放出アッセイ法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007117550A2 (en) * 2006-04-06 2007-10-18 Transave, Inc. Methods for coacervation induced liposomal encapsulation and formulations thereof
US20080089927A1 (en) * 2006-04-06 2008-04-17 Vladimir Malinin Methods for Coacervation Induced Liposomal Encapsulation and Formulations Thereof
US8702219B2 (en) 2008-12-18 2014-04-22 Hewlett-Packard Development Company, L.P. Pigmented ink-jet inks with gloss-enhancing polymers
US20150314002A1 (en) * 2012-11-29 2015-11-05 Insmed Incorporated Stabilized vancomycin formulations

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3787602A4

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12521345B1 (en) 2018-05-02 2026-01-13 Insmed Incorporated Large-scale manufacturing methods for aminoglycosides

Also Published As

Publication number Publication date
JP2021523224A (ja) 2021-09-02
EP3787602A1 (en) 2021-03-10
CA3098573A1 (en) 2019-11-07
CN112584821A (zh) 2021-03-30
US20210113467A1 (en) 2021-04-22
AU2019262117C1 (en) 2024-12-05
KR20210024451A (ko) 2021-03-05
US12521345B1 (en) 2026-01-13
JP7449275B2 (ja) 2024-03-13
JP2024075590A (ja) 2024-06-04
US20260096989A1 (en) 2026-04-09
AU2019262117A1 (en) 2020-11-19
EP3787602A4 (en) 2022-03-23
AU2019262117B2 (en) 2024-06-13

Similar Documents

Publication Publication Date Title
US12521345B1 (en) Large-scale manufacturing methods for aminoglycosides
US20220233447A1 (en) Manufacturing of bupivacaine multivesicular liposomes
JP2528153B2 (ja) リポソ―ム製剤および抗生物質
US11278494B1 (en) Manufacturing of bupivacaine multivesicular liposomes
US11357727B1 (en) Manufacturing of bupivacaine multivesicular liposomes
US20040101553A1 (en) Platinum aggregates and process for producing the same
JP2005525375A (ja) 生物活性物質をリポソーム又は脂質複合体内に封入する方法
BG108188A (bg) Воден състав на амфотерицин в
JP2021519777A5 (https=)
US20220233446A1 (en) Manufacturing of bupivacaine multivesicular liposomes
NO177774B (no) Fremgangsmåte for fremstilling av et preparat egnet for tilförsel av en hovedsakelig vannuopplöslig aktiv bestanddel
EP0488142B1 (de) Verfahren zur Verkapselung fester oder flüssiger, lipophiler Wirkstoffe zu diesen Wirkstoff enthaltenden Phospholipid-Liposomen sowie Arzneimittel diese Liposomen enthaltend
CA2511464C (en) Non-pegylated long-circulating liposomes
CN109077998B (zh) 沙美特罗脂质复合物及其制备方法
DK2252304T3 (en) PLATINUM UNITS AND PROCEDURES FOR PRODUCING THE SAME
DE69209830T2 (de) Hemmung der aggregaton arzneistoffhaltiger partikeln
WO2021110173A1 (en) Liposome formulation of fluticasone propionate
WO2021150471A1 (en) Liposome formulation of vilanterol trifenatate
CN109077997B (zh) 培美曲塞二钠脂质复合物及其制备方法
JPWO2019191627A5 (https=)
WO1997048381A1 (de) Pharmazeutische zubereitung in form von liposomen
WO2026088039A1 (en) Encapsulated apomorphine compositions
KR100795221B1 (ko) 암포테리신 β를 봉입하고 표면이 헤파린으로 수식된리포솜 및 그 제조 방법
JP2000302685A (ja) 抗腫瘍薬含有リポソーム製剤
JPH05212269A (ja) 安定なリポソーム水懸濁液

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19797021

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3098573

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2021510282

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2019262117

Country of ref document: AU

Date of ref document: 20190502

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20207034487

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2019797021

Country of ref document: EP

Effective date: 20201202

WWR Wipo information: refused in national office

Ref document number: 1020207034487

Country of ref document: KR