Biocompatible, stable and concentrated fluorocarbon emulsions for contrast enhancement and oxygen transport in internal animal use

• US 4,987,154 A
• Filed: 08/05/1987
• Issued: 01/22/1991
• Est. Priority Date: 01/14/1986
• Status: Expired due to Term

• Current Assignee: PFC Therapeutics, LLC
• Original Assignee: Alliance Pharmaceutical Corporation
• Inventors: Long, David M. Jr.
• Primary Examiner(s): Waddell, Frederick E.
• Application Number:
  US07/082,846
• Time in Patent Office: 1,266 Days
• Field of Search: 424/5, 514/832, 514/833, 514/772, 514/788
• US Class Current: 514/772
• CPC Class Codes: A61K 31/02 Halogenated hydrocarbons
• CPC Class Codes: A61K 9/0026 Blood substitute; Oxygen transporting formulations; Plasma extender
• CPC Class Codes: Y10S 977/738 Modified with biological, organic, or hydrocarbon material
• CPC Class Codes: Y10S 977/773 Nanoparticle, i.e. structure having three dimensions of 100 nm or less
• CPC Class Codes: Y10S 977/895 having step or means utilizing chemical property
• CPC Class Codes: Y10S 977/902 Specified use of nanostructure
• CPC Class Codes: Y10S 977/906 Drug delivery
• CPC Class Codes: Y10S 977/915 Therapeutic or pharmaceutical composition

Abstract

An up to 125% fluorocarbon emulsion for use in or with animal bodies and organs thereof, maintains emulsion stability through normal sterilization procedures with selective osmotic and buffering agents, maintains the emulsion at within predetermined osmolarity levels and, when desired, free of excessive calcium precipitation, reduces in vivo and in vitro red blood cell injury, reduces adverse anemia effects, reduces viscosity and reduces the rate of oxidation, and tends to equilibrate its distribution in major body organs thereby reducing toxicity. The osmotic agents may buffer and may provide nutrient in the form of sugars. The osmotic and buffering agents can comprise, selectively, hexahydric alcohols, namely mannitol and sorbitol; certain sugars, namely glucose, mannose and fructose; along with buffering agents that will affect osmolarity including imidazole, tris(hydroxymethyl)aminomethane, sodium chloride, sodium bicarbonate, monobasic potassium phosphate, dibasic potassium phosphate, calcium chloride, magnesium sulfate, monobasic sodium phosphate, dibasic sodium phosphate or combinations of them. The emulsion may include tocopherol. A method of emulsifying the fluorocarbon includes forced flow impingement under pressure after mixing the fluorocarbon into the discontinuous phase. The fluorocarbon emulsion can be used to deliver drugs and medicines soluble in, or transportable by the emulsion.

Claims

1. A fluorocarbon emulsion, prepared by:

combining an aqueous phase with an effective amount of emulsifying agent and a fluorocarbon to form a mixture having from greater than 50% to about 125% weight per volume of said fluorocarbon; and

passing the fluorocarbon-containing mixture through a mechanical emulsification apparatus in which said mixture is subjected to sufficiently high flow rates and pressures to form a stable, heat sterilizable fluorocarbon-in-water emulsion;

wherein said emulsion is biocompatible and exhibits substantial particle size stability in the non-frozen state following heat sterilization.

2. The emulsion of claim 1, wherein said emulsion further comprises an effective amount of an osmotic agent for adjusting and maintaining the osmolarity of the emulsion.

3. The emulsion of claim 1, which has been heat sterilized.

7. The fluorocarbon emulsion of claim 1 wherein the emulsifying agent is a phospholipid.

8. The fluorocarbon emulsion of claim 7 wherein the phospholipid is lecithin.

9. The fluorocarbon emulsion of claim 1 wherein the emulsifying agent is an anionic surfactant.

10. The fluorocarbon emulsion of claim 1 wherein the fluorocarbon is a mono-brominated perfluorocarbon.

11. The fluorocarbon emulsion of claim 10 wherein the mono-brominated perfluorocarbon is 1-bromoseptadecafluoroctane.

12. The fluorocarbon emulsion of claim 10 wherein the mono-brominated perfluorocarbon is 1-bromotridecafluorohexane.

13. The fluorocarbon emulsion of claim 10 wherein the mono-brominated perfluorocarbon is 1-bromopentadecafluoroseptane.

14. The fluorocarbon emulsion of claim 1 wherein the fluorocarbon is C4F9CH-CHC4F9.

15. The fluorocarbon emulsion of claim 1, wherein the fluorocarbon is F-decalin.

16. The fluorocarbon emulsion of claim 1 wherein the emulsifying agent comprises a biocompatible fluorinated surfactant.

17. The fluorocarbon emulsion of claim 16 wherein the fluorocarbon emulsion and fluorinated surfactant have a sufficient elimination rate that the fluorocarbon emulsion and fluorinated cosurfactant are substantially eliminated from the animal body or organ before carcinosis occurs.

18. The fluorocarbon emulsion of claim 16 wherein the fluorocarbon emulsion and fluorinated surfactant have a sufficient elimination rate that the fluorocarbon emulsion and fluorinated cosurfactant are substantially eliminated from the animal body or organ before teratogenesis occurs.

19. The fluorocarbon emulsion of claim 16 wherein the fluorocarbon emulsion and fluorinated surfactant have a sufficient elimination rate that the fluorocarbon emulsion and fluorinated cosurfactant are substantially eliminated from the animal body or organ before embryotoxicity occurs.

20. The fluorocarbon emulsion of claim 16 wherein the fluorinated cosurfactant comprises a fluorinated polyhydroxylated surfactant.

21. The fluorocarbon emulsion of claim 1 further comprising a buffering agent selected from the group consisting of imidazole, tris(hydroxymethyl)aminomethane, and combinations thereof.

22. The fluorocarbon emulsion of claim 21 wherein said buffering agent group further consists of sodium bicarbonate, monobasic sodium phosphate, dibasic sodium phosphate, magnesium sulfate, magnesium chloride, sodium chloride, potassium chloride, monobasic potassium phosphate, dibasic potassium phosphate and non-calcium precipitating combinations thereof.

23. The fluorocarbon emulsion of claim 21 wherein the pH of the emulsion is maintained at from approximately 4.0 to approximately 8.4 after sterilization and before use intravenously.

24. The fluorocarbon emulsion of claim 21 for use wherein the pH of the emulsion is maintained at from approximately 7.0 to approximately 7.8 before use in the coronary arteries.

25. The fluorocarbon emulsion of claim 21 wherein said buffering agent is imidazole.

26. The fluorocarbon emulsion of claim 1 further comprising an anti-oxidant.

27. The fluorocarbon emulsion of claim 26 wherein said anti-oxidant comprises mannitol.

28. The fluorocarbon emulsion of claim 26 wherein the anti-oxidant comprises a tocopherol.

29. The fluorocarbon emulsion of claim 26 wherein the anti-oxidant comprises mannitol and tocopherol.

30. The fluorocarbon emulsion of claim 28 wherein the tocopherol comprises alpha-tocopherol acetate.

31. The fluorocarbon emulsion of claim 26 including an anti-oxidant for reduction of oxidation of components of said emulsion comprising an effective amount of an anti-oxidant selected from the group consisting of ascorbyl palmitate, mannitol, tocopherol, imidazole and combinations thereof.

32. The fluorocarbon emulsion of claim 26 including an anti-oxidant for reduction of oxidation of tissues of animal bodies and organs thereof comprising an effective amount of an anti-oxidant selected from the group consisting of ascorbyl palmitate, mannitol, tocopherol, imidazole and combinations thereof.

33. The fluorocarbon emulsion of claim 1 for application to tissue of animal bodies and organs thereof, further comprising mannitol and tocopherol in an effective amount for reduction of oxidation in said emulsion.

34. The fluorocarbon emulsion of claim 1 for application to tissue of animal bodies and organs thereof, further comprising mannitol and tocopherolan in an effective amount for reduction of oxidation in said tissue of animal bodies and organs thereof.

35. The fluorocarbon emulsion of claim 1 for application to tissue of animal bodies and organs thereof, further comprising mannitol in an effective amount for reduction of oxidation in said emulsion.

36. The fluorocarbon emulsion of claim 1 for application to tissue of animal bodies and organs thereof, further comprising mannitol in an effective amount for reduction of oxidation in said tissue of animal bodies and organs thereof.

37. The fluorocarbon emulsion of claim 31 for application to tissue of animal bodies and organs thereof for reduction of oxidation therein wherein said anti-oxidant group further includes ascorbic acid, salts and complexes thereof and non-calcium precipitating combinations thereof.

38. The fluorocarbon emulsion of claim 1 wherein the fluorocarbon in emulsion is in an amount of from 80% weight per volume to 125% weight per volume.

39. The fluorocarbon emulsion of claim 2, wherein the osmolarity of the emulsion is maintained between from about 240 milliosmols to about 650 milliosmoles.

40. The fluorocarbon emulsion of claim 2, wherein the osmolarity of the emulsion is maintained between from about 300 milliosmols to about 450 milliosmols.

41. The fluorocarbon emulsion of claim 39 or 40, wherein the osmolarity is maintained, at least in part, by a hexahydric alcohol.

42. The fluorocarbon emulsion of claim 41, wherein the hexahydric alcohol is selected from the group consisting of mannitol and sorbitol.

43. The fluorocarbon emulsion of claim 42, wherein the hexahydric alcohol is mannitol, present at a concentration of from about 0.25% weight per volume to about 1.5% weight per volume.

44. The fluorocarbon emulsion of claim 39 or 40, wherein the osmolarity is maintained, at least in part, by a sugar.

45. The fluorocarbon emulsions of claim 44, wherein the sugar is selected from the group consisting of glucose, mannose and fructose, or combinations thereof.

46. The fluorocarbon emulsion of claim 39 or 40, wherein the osmolarity is maintained, at least in part, by a buffering agent.

47. The fluorocarbon emulsion of claim 39 or 40, wherein the osmolarity is maintained, at least in part, by chloride or sulfate salts.

4. A storage stable, heat sterilizable fluorocarbon emulsion, comprising:

an continuous aqueous phase, a discontinuous fluorocarbon phase, and an effective amount of emulsifying agent, wherein the concentration of said fluorocarbon phase in said emulsion is greater than 75% and no more than 125%, weight per volume, and wherein said emulsion exhibits substantial particle size stability on storage in the non-frozen state following heat sterilization and is biocompatible.

5. The emulsion of claim 4, wherein the concentration of said fluorocarbon phase in said emulsion is at least about 80%, weight per volume.

6. The emulsion of claim 4, wherein the concentration of said fluorocarbon phase in said emulsion is at least about 100%, weight per volume.