Method of preparing gas and gaseous precursor-filled microspheres

• US 5,585,112 A
• Filed: 11/30/1993
• Issued: 12/17/1996
• Est. Priority Date: 12/22/1989
• Status: Expired due to Term

• Current Assignee: Lantheus Medical Imaging, Inc. (Lantheus Holdings, Inc.)
• Original Assignee: Imarx Pharmaceutical Corp. (Sycamore Entertainment Group, Inc.)
• Inventors: Ramaswami, VaradaRajan, Yellowhair, David, Matsunaga, Terry, Fritz, Thomas A., Unger, Evan C., Wu, Guanli
• Primary Examiner(s): Kishore, Gollamudi S.
• Application Number:
  US08/159,687
• Time in Patent Office: 1,113 Days
• Field of Search: 424/450, 424/9, 428/402.2, 264/4.1, 264/4.3, 128/654
• US Class Current: 424/450
• CPC Class Codes: A61K 41/0028 Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
• CPC Class Codes: A61K 41/0052 Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
• CPC Class Codes: A61K 49/1815 compo-inhalant, e.g. breath tests
• CPC Class Codes: A61K 49/22 Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 49/227 Liposomes, lipoprotein vesicles, e.g. LDL or HDL lipoproteins, micelles, e.g. phospholipidic or polymeric
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/1277 Processes for preparing; Proliposomes
• CPC Class Codes: A61K 9/1278 Post-loading, e.g. by ion or pH gradient
• CPC Class Codes: A61M 5/3145 Filters incorporated in syringes
• CPC Class Codes: Y10S 424/812 Liposome comprising an antibody, antibody fragment, antigen, or other specific or nonspecific immunoeffector
• CPC Class Codes: Y10S 436/829 Liposomes, e.g. encapsulation
• CPC Class Codes: Y10S 977/907 Liposome
• CPC Class Codes: Y10S 977/915 Therapeutic or pharmaceutical composition
• CPC Class Codes: Y10S 977/927 Diagnostic contrast agent
• CPC Class Codes: Y10S 977/929 Ultrasound contrast agent

Abstract

Methods of and apparatus for preparing temperature activated gaseous precursor-filled liposomes are described. Gaseous precursor-filled liposomes prepared by these methods are particularly useful, for example, in ultrasonic imaging applications and in therapeutic drug delivery systems.

Claims

1. Gaseous precursor-filled liposomes prepared by a gel state shaking gaseous precursor instillation method, said method comprising adding a lipid to an aqueous solution or suspension, shaking said lipid-containing aqueous solution or suspension in the presence of a temperature activated gaseous precursor at a temperature below the gel state to liquid crystalline state phase transition temperature of the lipid, wherein said gaseous precursor is a fluorine-containing gaseous precursor, said fluorine-containing gaseous precursor selected from the group consisting of perfluorocarbons, fluorohydrocarbons, and sulfur hexafluoride, wherein upon activation of said gaseous precursor to a gas said liposomes have at least about a 90% volume of gas in the interior thereof.

20. The gaseous precursor-filled liposomes of claim 1 for use with a nebulizer, said liposomes targeted to the lung.

2. Gas-filled liposomes prepared by a gel state shaking gas instillation method, said liposomes comprising a lipid and a fluorine-containing gas, said fluorine-containing gas selected from the group consisting of perfluorocarbons, fluorohydrocarbons, and sulfur hexafluoride, said liposomes prepared by a method comprising adding a lipid to an aqueous solution or suspension, shaking said lipid-containing aqueous solution or suspension in the presence of a temperature activated gaseous precursor at a temperature below the gel state to liquid crystalline state phase transition temperature of the lipid, said liposomes having at least about a 90% volume of gas in the interior thereof.

3. The liposomes of claim 2 wherein said lipid is selected from the group consisting of fatty acids;

lysolipids;

sphingolipids;

glycolipids;

glucolipids;

sulfatides;

glycosphingolipids;

lipids with ether and ester-linked fatty acids, polymerized lipids, phospholipids with short chain fatty acids of 6-8 carbons in length, and synthetic phospholipids with asymmetric acyl chains.

4. The liposomes of claim 3 wherein said polymer is between 400 and 200,000 molecular weight.

5. The liposomes of claim 3 wherein said polymer is between 1,000 and 20,000 molecular weight.

6. The liposomes of claim 3 wherein said polymer is between 2,000 and 8,000 molecular weight.

7. The liposomes of claim 3 wherein said lipid bearing a covalently bound polymer comprises compounds of the formula XCHY--(CH₂)n--O--(CH₂)n--YCHX wherein X is an alcohol group, Y is OH or an alkyl group and n is 0 to 10,000.

8. The liposomes of claim 3 wherein said polymer is selected from the group consisting of polyethyleneglycol, polyvinylpyrrolidone, polyvinylalcohol and polypropyleneglycol.

9. The liposomes of claim 3 wherein said polymer is polyethyleneglycol.

10. The liposomes of claim 3 wherein said lipid comprises from about 1 mole % to about 20 mole %.

11. The gas-filled liposomes of claim 2 wherein said fluorine-containing gas is selected from the group consisting of fluorine gas, 1-fluorobutane, hexafluoro acetone, tetrafluoroallene, boron trifluoride, 1,2,3-trichloro, 2-fluoro-1,3-butadiene, hexafluoro-1,3-butadiene, 1-fluoro-butane, 1,2,3-trichloro, 2-fluoro-1,3-butadiene, hexafluoro-1,3-butadiene, 1-fluoro-butane, decafluoro butane, perfluoro-1-butene, perfluoro-1-butene, perfluoro-2-butene, 2-chloro-1,1,1,4,4,4-hexafluoro-butyne, perfluoro-2-butyne, octafluoro-cyclobutane, perfluoro-cyclobutene, perfluoroethane, perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, 1,1,1-trifluorodiazoethane, hexafluoro-dimethyl amine, perfluorodimethylamine, 4-methyl,1,1,1,2-tetrafluoro ethane, 1,1,1-trifluoroethane, 1,1,2,2-tetrafluoroethane, 1,1,2-trichloro-1,2,2-trifluoroethane, 1,1-dichloro-1,2,2,2-tetrafluoro ethane, 1,2-difluoro ethane, 1-chloro-1,1,2,2,2-pentafluoro ethane, 2-chloro, 1,1-difluoroethane, 1-chloro-1,1,2,2-tetrafluoro ethane, 2-chloro, 1,1-difluoroethane, chloropentafluoro ethane, dichlorotrifluoroethane, fluoro-ethane, hexafluoro-ethane, nitro-pentafluoro ethane, nitroso-pentafluoro ethane, perfluoro ethane, perfluoro ethylamine, 1,1-dichloro-1,2-difluoro ethylene, 1,2-difluoro ethylene, methane-sulfonyl chloride-trifluoro, methanesulfonyl fluoride-trifluoro, methane-(pentafluorothio)trifluoro, methane-bromo difluoro nitroso, methane-bromo fluoro, methane-bromo chloro-fluoro, methanebromo-trifluoro, methane-chloro difluoro nitro, methanechloro fluoro, methane-chloro trifluoro, methane-chloro-difluoro, methane dibromo difluoro, methane-dichloro difluoro, methane-dichloro-fluoro, methanedifluoro, methane-difluoro-iodo, methane-fluoro, methane-iodo-trifluoro, methane-nitro-trifluoro, methane-nitroso-trifluoro, methane-tetrafluoro, methane-trichlorofluoro, methane-trifluoro, methanesulfenylchloride-trifluoro, pentane-perfluoro, 1-pentane-perfluoro, propane-1, 1, 1, 2, 2, 3-hexafluoro, propane-2,2 difluoro, propane-heptafluoro-1-nitro, propane-heptafluoro-1-nitroso, propane-perfluoro, propyl-1,1,1,2,3,3-hexafluoro-2,3 dichloro, propylene-3-fluoro, propylene-perfluoro, propyne-3,3,3-trifluoro, styrene-3-fluoro, sulfur hexafluoride, sulfur (di)-decafluoro, trifluoroacetonitrile, trifluoromethyl peroxide, trifluoromethyl sulfide, tungsten hexafluoride, pentafluoro octadecyl iodide, perfluorooctylbromide, perfluorodecalin, perfluorododecalin, perfluorooctyliodide, perfluorotripropylamine, perfluorotributylamine, hexafluoropropylene, bromochlorofluoromethane, octafluoropropane, 1,1 dichloro, fluoro ethane, hexa- fluoroethane, hexafluoro-2-butyne, perfluoropentane, perfluorobutane, octafluoro-2-butene, hexafluorobuta-1,3-diene, and octafluorocyclopentene.

12. The gas-filled liposomes of claim 11 wherein said fluorine-containing gas is selected from the group consisting of fluorine gas, perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, sulfur hexafluoride, hexafluoropropylene, octafluoropropane, perfluorocyclobutane, octafluorocyclopentene, dodecafluoropentane, and octafluorocyclobutane.

13. The liposomes of claim 12 wherein said fluorine-containing gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, perfluorocyclobutane, and sulfur hexafluoride.

14. The liposomes of claim 13 wherein said fluorine-containing gas is selected from the group consisting of perfluoropropane, perfluorocyclobutane, and perfluorobutane.

15. The liposomes of claim 14 wherein said fluorine-containing gas is perfluoropropane.

16. The liposomes of claim 2 wherein said fluorine-containing gas is a perfluorocarbon gas.

17. The liposomes of claim 16 wherein said perfluorocarbon gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, and perfluorocyclobutane.

18. The liposomes of claim 17 wherein said perfluorocarbon gas is selected from the group consisting of perfluoropropane, perfluorocyclobutane, and perfluorobutane.

19. The liposomes of claim 18 wherein said perfluorocarbon gas is perfluoropropane.

21. The liposomes of claim 2 wherein said lipid is selected from the group consisting of phosphatidylcholine, dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipentadecanoylphosphatidylcholine, dilauroylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, phosphatidylethanolamine, dioleoylphosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, sphingomyelin, ganglioside GM1, ganglioside GM2, phosphatidic acid, palmitic acid, stearic acid, arachidonic acid, oleic acid, lipids bearing polyethyleneglycol, chitin, hyaluronic acid or polyvinylpyrrolidone, cholesterol, cholesterol sulfate, cholesterol hemisuccinate, tocopherol hemisuccinate, diacetyl phosphate, stearylamine, cardiolipin, 6-(5-cholesten-3β

-yloxy)-1-thio-β

-D-galactopyranoside, digalactosyldiglyceride, 6-(5-cholesten-3β

-yloxy)hexyl-6-amino-6-deoxy-1-thio-β

-D-galactopyranoside, 6-(5-cholesten-3β

-yloxy)hexyl-6-amino-6-deoxyl-1-thio-α

-D-mannopyranoside, 12-(((7'"'"'-diethylaminocoumarin-3-yl)carbonyl)methylamino)-octadecanoic acid, N-[12-(((7'"'"'-diethylaminocoumarin-3-yl)carbonyl)methyl-amino) octadecanoyl]-2-aminopalmitic acid, cholesteryl)4'"'"'-trimethyl-ammonio)butanoate, N-succinyldioleoylphosphatidylethanol-amine, 1,2-dioleoyl-sn-glycerol,1,2-dipalmitoyl-sn-3-succinylglycerol, 1,3-dipalmitoyl-2-succinylglycerol,1-hexadecyl-2-palmitoylglycerophosphoethanolamine, palmitoylhomocysteine, lauryltrimethylammonium bromide, cetyltrimethylammonium bromide, myristyltrimethylammonium bromide, alkyldimethylbenzylammonium chloride, benzyldimethyldodecylammonium bromide, benzyldimethylhexadecylammonium bromide, benzyldimethyltetradecylammonium bromide, cetyldimethylethylammonium bromide, cetylpyridinium bromide, pentafluoro octadecyl iodide, perfluorooctylbromide, perfluorodecalin, perfluorododecalin, perfluorooctyliodide, perfluorotripropylamine, and perfluorotributylamine.