Charged lipids and uses for the same

• US 6,120,751 A
• Filed: 09/08/1997
• Issued: 09/19/2000
• Est. Priority Date: 03/21/1997
• Status: Expired due to Fees

• Current Assignee: Imarx Therapeutics, Inc. (Sycamore Entertainment Group, Inc.)
• Original Assignee: Imarx Pharmaceutical Corp. (Sycamore Entertainment Group, Inc.)
• Inventors: Unger, Evan C.
• Primary Examiner(s): Dees, Jose' G.
• Assistant Examiner(s): Hartley, Michael G.
• Application Number:
  US08/925,353
• Time in Patent Office: 1,107 Days
• Field of Search: 424/450, 424/9.52, 424/9.51, 424/489, 424/498, 424/502, 424/1.21, 424/9.321, 424/812, 514/937, 264/4, 264/4.1, 264/4.32, 264/4.33, 427/2.14, 427/213.3, 427/213.31, 428/402, 428/402.24, 428/402.2, 436/829
• US Class Current: 424/9.51
• 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 47/544 Phospholipids
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: Y10T 428/2984 Microcapsule with fluid core [includes liposome]

Abstract

The present invention is directed to charged lipids, compositions comprising charged lipids, and the use of these compositions in drug delivery, targeted drug delivery, therapeutic imaging and diagnostic imaging, as well as their use as contrast agents.

Claims

1. A contrast agent comprising a cochleate which comprises a charged lipid, a counter ion, a lipid covalently bonded to a polymer, and a gas, a gaseous precursor or a gas and a gaseous precursor, wherein the gas and gaseous precursor comprise fluorinated compounds.

2. The contrast agent of claim 1, wherein the charged lipid is an anionic lipid and the counter ion is a cationic counter ion.

3. The contrast agent of claim 2, wherein the anionic lipid is selected from the group consisting of a phosphatidic acid, a phosphatidyl glycerol, a phosphatidyl glycerol fatty acid ester, a phosphatidyl ethanolamine anandamide, a phosphatidyl ethanolamine methanandamide, a phosphatidyl serine, a phosphatidyl inositol, a phosphatidyl inositol fatty acid ester, a cardiolipin, a phosphatidyl ethylene glycol, an acidic lysolipid, a sulfolipid, a sulfatide, a saturated free fatty acid, an unsaturated free fatty acid, a palmitic acid, a stearic acid, an arachidonic acid, an oleic acid, a linolenic acid, a linoleic acid, and a myristic acid.

4. The contrast agent of claim 2, wherein the cationic counter ion is selected from the group consisting of Be²⁺, Mg²⁺, Ca²⁺, Sr2+, Ba²⁺, Al³⁺, Ga³⁺, Ge³⁺, Sn⁴⁺, Pb²⁺, Pb⁴⁺, Ti³⁺, Ti⁴⁺, V²⁺, V³⁺, Cr²⁺, Cr³⁺, Mn²⁺, Mn³⁺, Fe²⁺, Fe³⁺, Co²⁺, Co³⁺, Ni²⁺, Ni³⁺, Cu²⁺, Zn²⁺, Zr⁴⁺, Nb³⁺, Mo²⁺, Mo³⁺, Cd²⁺, In³⁺, W²⁺, W⁴⁺, Os²⁺, Os³⁺, Os⁴⁺, Ir²⁺, Ir³⁺, Ir⁴⁺, Hg²⁺, Bi³⁺, La³⁺, and Gd³⁺.

5. The contrast agent of claim 4, wherein the cationic counter ion is selected from the group consisting of Ca²⁺, Mg²⁺, Zn²⁺, Mn²⁺ and Gd³⁺.

6. The contrast agent of claim 5, wherein the cationic counter ion is Ca²⁺.

7. The contrast agent of claim 1, wherein, in the lipid covalently bonded to the polymer, the polymer is selected from the group consisting of polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, polypropylene glycol, a polyvinylalkylether, a polyacrylamide, a polyalkyloxazoline, a polyhydroxyalkyloxazoline, a polyphosphazene, a polyoxazolidine, a polyaspartamide, a polymer of sialic acid, a polyhydroxyalkyl(meth)acrylate and a poly(hydroxyalkylcarboyxlic acid).

8. The contrast agent of claim 7, wherein, in the lipid covalently bonded to the polymer, the polymer is polyethylene glycol.

9. The contrast agent of claim 8, wherein the polyethylene glycol has a molecular weight of from about 1,000 to about 10,000.

10. The contrast agent of claim 1, wherein the lipid covalently bonded to the polymer is selected from the group consisting of

dipalmitoylphosphatidylethanolamine-polyethylene glycol,

dioleoylphosphatidylethanolamine-polyethylene glycol and

distearylphosphatidylethanolamine-polyethylene glycol.

11. The contrast agent of claim 2, wherein the anionic lipid is dipalmitoyl-phosphatidic acid, the cationic counter ion is Ca²⁺ and the lipid covalently bonded to the polymer is dipalmitoylphosphatidylethanolamine-polyethylene glycol.

12. The contrast agent of claim 1, further comprising at least one lipid having a neutral charge.

13. The contrast agent of claim 1, further comprising a targeting ligand.

14. The contrast agent of claim 13, wherein the targeting ligand is selected from the group consisting of peptides, proteins and saccharides.

15. The contrast agent of claim 1, wherein the fluorinated compound is selected from the group consisting of a perflurocarbon, sulfur hexafluoride and a perfluoroether.

16. The contrast agent of claim 15, wherein the fluorinated compound is a perfluorocarbon selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorocyclopropane, perfluorobutane, perfluorocyclobutane, perfluoropentane and perfluorocyclopentane.

17. The contrast agent of claim 15, wherein the fluorinated compound is a perfluoroether selected from the group consisting of perfluorotetrahydropyran, perfluoromethyltetrahydrofuran, perfluorobutylmethyl ether, perfluoropropylethyl ether, perfluorocyclobutylmethyl ether, perfluorocyclopropylethyl ether, perfluoropropylmethyl ether, perfluorodiethyl ether, perfluorocyclopropylmethyl ether, perfluoromethylethyl ether and perfluorodimethyl ether.

18. The contrast agent of claim 1, further comprising a fluorinated liquid.

19. The contrast agent of claim 18, wherein the fluorinated liquid is selected from the group consisting of perfluorohexane, perfluoroheptane, perfluorooctane, perfluorononane, perfluorodecane, perfluorododecane, perfluorocyclohexane, perfluorodecalin, perfluorododecalin, perfluorooctyliodide, perfluorooctylbromide, perfluorotripropylamine, perfluorotributylamine, perfluorobutylethyl ether, bis(perfluoroisopropyl) ether and bis(perfluoropropyl) ether.

20. A contrast agent of claim 1 wherein said cochleate is in the form of a spiral or tubule.