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Details for Patent: 6,315,981

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Details for Patent: 6,315,981

Title: Gas filled microspheres as magnetic resonance imaging contrast agents
Abstract:Novel gas filled microspheres useful as magnetic resonance imaging (MRI) contrast agents are provided.
Inventor(s): Unger; Evan C. (Tucson, AZ)
Assignee: Imarx Therapeutics, Inc. (Tucson, AZ)
Filing Date:Mar 19, 1999
Application Number:09/272,468
Claims:1. A contrast medium for magnetic resonance imaging, said contrast medium comprising gas filled liposomes wherein said liposomes are prepared by a method which comprises the step of agitating an aqueous suspension of a biocompatible lipid in the presence of a gas, at a temperature below the gel to liquid crystalline phase transition temperature of the biocompatible lipid, until gas filled liposomes result, wherein said gas is hyperpolarized rubidium entriched xenon.

2. A contrast medium according to claim 1 wherein the biocompatible lipid is selected from the group consisting of fatty acids, lysolipids, phosphatidylcholines, phosphatidylethanolamines, phosphatidylserines, phosphatidylglycerols, phosphatidylinositols, sphingolipids, glycolipids, glucolipids, sulfatides, glycosphingolipids, phosphatidic acids, palmitic acids, stearic acids, arachidonic acids, oleic acids, lipids bearing polymers, lipids bearing sulfonated monosaccharides, lipids bearing sulfonated disaccharides, lipids bearing sulfonated oligosaccharides, lipids bearing sulfonated polysaccharides, cholesterols, tocopherols, lipids with ether-linked fatty acids, lipids with ester-linked fatty acids, polymerized lipids, diacetyl phosphates, dicetyl phosphates, stearylamines, cardiolipin, phospholipids with fatty acids of 6-8 carbons in length, synthetic phospholipids with asymmetric acyl chains, ceramides, non-ionic lipids, sterol aliphatic acid esters, sterol esters of sugar acids, esters of sugar acids, esters of sugar alcohols, esters of sugars, esters of aliphatic acids, saponins, glycerol dilaurate, glycerol trilaurate, glycerol dipalmitate, glycerol, glycerol esters, alcohols of 10-30 carbons in length, 6-(5-cholesten-3.beta.-yloxy)-1-thio-.beta.-D-galactopyranoside, digalactosyldiglyceride, 6-(5-cholesten-3.beta.-yloxy)hexyl-6-amino-6-deoxy-1-thio-.beta.-D-galacto pyranoside, 6-(5-cholesten-3.beta.-yloxy)hexyl-6-amino-6-deoxyl-1-thio-.alpha.-D-manno pyranoside, 12-(((7'-diethylaminocoumarin-3-yl)carbonyl)methylamino)-octadecanoic acid, N-[12-(((7'-diethylaminocoumarin-3-yl)carbonyl)methyl-amino)octadecanoyl]- 2-aminopalimitic 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, cationic lipids, N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammoium chloride, 1,2-dioleoyloxy-3-(trimethylammonio)propane, 1,2-dioleoyl-3-(4'-trimethyl-ammonio)butanoyl-sn-glycerol, lipids bearing cationic polymers, alkyl phosphonates, alkyl phosphinates, and alkyl phosphites.

3. A contrast medium according to claim 2 wherein the phosphatidylcholine is selected from the group consisting of dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipentadecanoylphosphatidylcholine, dilauroylphosphatidylcholine, dipalmitoylphosphatidylcholine, and distearoylphosphatidylcholine; wherein the phosphatidylethanolamine is selected from the group consisting of dipalmitoylphosphatidylethanolamine and dioleoylphosphatidylethanolamine; wherein the sphingolipid is sphingomyelin; wherein the glycolipid is selected from the group consisting of ganglioside GM1 and ganglioside GM2; wherein in the lipids bearing polymers the polymer is selected from the group consisting of polyethyleneglycol, chitin, hyaluronic acid and polyvinylpyrrolidone; wherein the sterol aliphatic acid esters are selected from the group consisting of cholesterol sulfate, cholesterol butyrate, cholesterol isobutyrate, cholesterol palmitate, cholesterol stearate, lanosterol acetate, ergosterol palmitate, and phytosterol n-butyrate; wherein the sterol esters of sugar acids are selected from the group consisting of cholesterol glucuronide, lanosterol glucuronide, 7-dehydrocholesterol glucuronide, ergosterol glucuronide, cholesterol gluconate, lanosterol gluconate, and ergosterol gluconate; wherein the esters of sugar acids and the esters of sugar alcohols are selected from the group consisting of lauryl glucuronide, stearoyl glucuronide, myristoyl glucuronide, lauryl gluconate, myristoyl gluconate, and stearoyl gluconate; wherein the esters of sugars and the esters of aliphatic acids are selected from the group consisting of sucrose laurate, fructose laurate, sucrose palmitate, sucrose stearate, glucuronic acid, gluconic acid, accharic acid, and polyuronic acid; wherein the saponins are selected from the group consisting of sarsasapogenin, smilagenin, hederagenin, oleanolic acid, and digitoxigenin; wherein the glycerol esters are selected from the group consisting of glycerol tripalmitate, glycerol distearate, glycerol tristearate, glycerol dimyristate, glycerol and trimyristate; wherein the alcohols of 10-30 carbon length are selected from the group consisting of n-decyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, and n-octadecyl alcohol; wherein in the lipids bearing cationic polymers the cationic polymers are selected from the group consisting of polylysine and polyarginine.

4. A contrast medium according to claim 1 wherein the lipid is selected from the group consisting of dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine, and dipalmitoylphosphatidic acid.

5. A contrast medium according to claim 4 wherein the polymer polyethylene glycol is bound to said dipalmitoyl-phosphatidylethanolamine.

6. A contrast medium according to claim 1 wherein the lipid comprises dipalmitoylphosphatidylethanolamine and phosphatidic acid in a total amount of from about 0.5 to about 30 mole percent.

7. A contrast medium according to claim 1 wherein the lipid comprises a lipid selected from the group consisting of dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine, in an amount of from about 70 to about 100 mole percent.

8. A contrast medium according to claim 1 wherein the lipid comprises: (i) a neutral lipid, (ii) a negatively charged lipid, and (iii) a lipid bearing a hydrophilic polymer; wherein the amount of said negatively charged lipid is greater than 1 mole percent of total lipid present and the amount of lipid bearing a hydrophilic polymer is greater than 1 mole percent of total lipid present.

9. A contrast medium according to claim 8 wherein the negatively charged lipid is phosphatidic acid and wherein the polymer in the lipid bearing a hydrophilic polymer is has a weight average molecular weight of from about 400 to about 100,000 and is covalently bound to said lipid.

10. A contrast medium according to claim 9 wherein said hydrophilic polymer of said lipid bearing hydrophilic polymer is selected from the group consisting of polyethyleneglycol, polypropyleneglycol, polyvinylalcohol, and polyvinylpyrrolidone and copolymers thereof, and wherein said lipid of said lipid bearing a hydrophilic polymer is selected from the group consisting of dipalmitoyl-phosphatidylethanolamine and distearoylphosphatidyl-ethanolamine.

11. A contrast medium according to claim 1 wherein the lipid comprises about 77.5 mole percent dipalmitoyl-phosphatidylcholine, about 12.5 mole percent of dipalmitoylphosphatidic acid, and about 10 mole percent of dipalmitoylphosphatidylethanolamine-polyethyleneglycol 5000.

12. A contrast medium according to claim 1 wherein the lipid comprises about 82 mole percent dipalmitoylphosphatidylcholine, about 10 mole percent of dipalmitoylphosphatidic acid, and about 8 mole percent of dipalmitoylphosphatidylethanolamine-polyethyleneglycol 5000.

13. A contrast medium according to claim 1 wherein the contrast medium further comprises a contrast agent.

14. A contrast medium according to claim 13 wherein the contrast agent is selected from the group consisting of paramagnetic and superparamagnetic agents.

15. A contrast medium according to claim 14 wherein the contrast agent is a paramagnetic agent.

16. A contrast medium according to claim 15 wherein the paramagnetic agent comprises a paramagnetic ion selected from the group consisting of transition, lanthanide and actinide elements.

17. A contrast medium according to claim 16 wherein the paramagnetic ion is selected from the group consisting of Gd(III), Mn(II), Cu(II), Cr(III), Fe(II), Fe(III), Co(II), Er(II), Ni(II), Eu(III) and Dy(III).

18. A contrast medium according to claim 17 wherein the paramagnetic ion is Mn(II).

19. A contrast medium according to claim 15 wherein the paramagnetic ion is in the form of a salt.

20. A contrast medium according to claim 15 wherein the paramagnetic ion is bound to a complexing agent or a proteinaceous macromolecule.

21. A contrast medium according to claim 15 wherein the paramagnetic agent comprises a nitroxide.

22. A contrast medium according to claim 14 wherein the contrast agent is a superparamagnetic agent.

23. A contrast medium according to claim 22 wherein the superparamagnetic agent comprises a metal oxide or metal sulfide.

24. A contrast medium according to claim 23 wherein the superparamagnetic agent comprises a metal oxide wherein the metal is iron.

25. A contrast medium according to claim 22 wherein the superparamagnetic agent is ferritin, iron, magnetic iron oxide, .gamma.-Fe.sub.2 O.sub.3, manganese ferrite, cobalt ferrite and nickel ferrite.

26. A contrast medium according to claim 1 further comprising compounds selected from the group consisting of ingestible oils; mixed micelle systems compounds; viscosity modifiers; emulsifying and/or solubilizing agents; suspending or viscosity-increasing agents; synthetic suspending agents; and tonicity-raising agents.

27. A contrast medium according to claim 1 wherein the microspheres are prepared from a composition comprising dipalmitoylphosphatidylcholine, glycerol and propylene glycol.

28. A method of preparing gas filed liposomes for use as a magnetic resonance imaging contrast medium, said method comprising the step of agitating an aqueous suspension of a biocompatible lipid in the presence of a gas, at a temperature below the gel to liquid crystalline phase transition temperature of the biocompatible lipid, unitl said gas filled liposomes result, wherein said gas is hyperpolarized rubidium enriched xenon.

29. A method according to claim 28 wherein the step of agitating comprises shaking or vortexing.

30. A method according to claim 29 wherein the shaking comprises a reciprocating motion in the form of an arc.

31. A method according to claim 30 wherein the arc is between about 2.degree. and about 20.degree., and the number of reciprocations per minute is between about 1000 and about 20,000.

32. A method according to claim 31 wherein the arc is between about 6.degree. and about 7.degree., and the number of reciprocations per minute is between about 5000 and about 8000.

33. A method of providing an image of an internal region of a patient comprising (i) administering to the patient a contrast medium according to claim 1, and (ii) scanning the patient using magnetic resonance imaging to obtain visible images of said region.

34. A method according to claim 33 wherein the region is the vasculature.

35. A method according to claim 33 wherein the region is the cardiovascular region.

36. A method according to claim 33 wherein the region is the gastrointestinal region.

37. A method for diagnosing the presence of diseased tissue in a patient comprising (i) administering to the patient a contrast medium according to claim 1, and (ii) scanning the patient using magnetic resonance imaging to obtain visible images of any diseased tissue in the patient.

38. A method according to claim 37 wherein the scanning is of the vasculature of the patient.

39. A method according to claim 37 wherein the scanning is of the cardiovascular region of the patient.

40. A method according to claim 37 wherein the scanning is of the gastrointestinal region of the patient.

41. A method according to claim 37 wherein the scanning is of a region of the patient selected from the following:

intranasal tract; auditory canal; intraocular region; intraperitoneal region; kidneys; urethra; and genitourinary tract.

42. A method of providing an image of an internal region of a patient comprising (i) administering to the patient the contrast medium of claim 19, and (ii) scanning the patient using magnetic resonance imaging to obtain visible images of said region.

43. A method for diagnosing the presence of diseased tissue in a patient comprising (i) administering to the patient the contrast medium of claim 19, and (ii) scanning the patient using magnetic resonance imaging to obtain visible images of any diseased tissue in the patient.
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