Apparatus and method for making gas-filled vesicles of optimal size

• US 5,656,211 A
• Filed: 06/07/1995
• Issued: 08/12/1997
• 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: Yellowhair, David, Unger, Evan, McCreery, Thomas, Barrette, Terrence R.
• Primary Examiner(s): Nutter, Nathan M.
• Application Number:
  US08/482,294
• Time in Patent Office: 797 Days
• Field of Search: 264/4.1, 264/4.3, 264/4.5, 424/489, 424/490, 424/491, 424/501
• US Class Current: 264/4.1
• CPC Class Codes: A61J 3/00 Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
• CPC Class Codes: A61K 2800/87 Application Devices; Containers; Packaging
• 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: B01F 23/23 by introducing gases into liquid media, e.g. for producing aerated liquids
• CPC Class Codes: B01F 31/25 the containers being submitted to a combination of movements other than within a horizontal plane, e.g. rectilinear and pivoting movement with a receptacle submitted to a combination of movements, i.e. at least one movement being vibratory or oscillatory B01F31/50
• CPC Class Codes: B01F 31/50 with a receptacle submitted to a combination of movements, i.e. at least one vibratory or oscillatory movement
• CPC Class Codes: B01F 33/5014 movable by human force, e.g. kitchen or table devices
• CPC Class Codes: B01F 35/30 Driving arrangements; Transmissions; Couplings; Brakes
• CPC Class Codes: Y10S 366/605 Paint mixer

Abstract

A method and apparatus for making vesicles suitable for use as contrast agents in which a container containing an aqueous suspension phase and a separate gas phase is shaken using reciprocating motion. The reciprocating motion is produced by a shaker arm that moves the container in two, substantially perpendicular directions, with the motion in the first direction being along an arcuate path. The overall path of the motion occurs in a figure-8 eight pattern. The frequency of shaking is at least approximately 2800 RPM, the length of the shaker arm is at least approximately 6 cm, and the angle through which the shaker arm rotates in the first direction is at least approximately 3°. The total length of travel around the figure-8 pattern is at least 0.7 cm.

Claims

1. A method of making vesicles, comprising the steps of:

a) placing an aqueous suspension phase and a gaseous phase substantially separate from said aqueous suspension phase in a container; and

b) shaking said container by imparting a reciprocating motion thereto until vesicles are formed.

2. The method according to claim 1, wherein the amplitude of said reciprocating motion is at least approximately 0.3 cm.

3. The method according to claim 2, wherein the amplitude of said reciprocating motion is no greater than approximately 2.5 cm.

4. The method according to claim 1, wherein the total length of travel of said container during said reciprocating motion is at least approximately 0.7 cm.

5. The method according to claim 1, wherein the frequency of said reciprocating motion is at least approximately 2800 RPM.

6. The method according to claim 2, wherein the frequency of said reciprocating motion is no greater than approximately 4500 RPM.

7. The method according to claim 1, wherein said reciprocating motion occurs in at least a first direction, said motion in said first direction occurring along an arcuate path.

8. The method according to claim 7, wherein the angle of rotation encompassed by said arcuate path is at least approximately 3°

.

9. The method according to claim 8, wherein the angle encompassed by said arcuate path is no greater than approximately 9°

.

10. The method according to claim 7, wherein the radius of curvature of said arcuate path is at least approximately 6 cm.

11. The method according to claim 10, wherein the radius of curvature of said arcuate path is no greater than approximately 15 cm.

12. The method according to claim 1, wherein said reciprocating motion comprises motion in first and second substantially perpendicular directions.

13. The method according to claim 12, wherein said reciprocating motion occurs along a path having approximately a figure-8 pattern.

14. The method according to claim 13, wherein the total length of travel of said container around said figure-8 pattern is at least approximately 0.7 cm.

15. The method according to claim 1, wherein said aqueous suspension phase comprises lipids.

16. The method according to claim 15, wherein said aqueous suspension phase comprises

dipalmitoylphosphatidylcholine, dipalmitoylphosphatidic acid, and dipalmitoylphosphatidylethanolamine.

17. The method according to claim 16, wherein said gaseous phase comprises a perfluorocarbon gas.

18. The method according to claim 1, wherein said gas phase initially occupies at least 10% of the volume of said container.

19. The method according to claim 1, wherein said shaking produces vesicles of which 95% are smaller than 10 μ

m.

20. The method according to claim 19, wherein the duration of said shaking is no greater than approximately 2 minutes.

21. The method according to claim 1, wherein said shaking produces vesicles having a mean size of less than 2.5 μ

m.

22. The method according to claim 1, wherein said container is a syringe.

23. The method according to claim 1 wherein said vesicles comprise a monolayer.

24. The method according to claim 23 wherein said monolayer comprises a phospholipid.

25. The method according to claim 24 wherein said gaseous phase is selected from the group consisting of perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, and sulfur hexafluoride.

26. The method according to claim 24 wherein said monolayer comprises a phospholipid and said gaseous phase is perfluoropentane.

27. The method according to claim 24 wherein said monolayer comprises a phospholipid and said gaseous phase is sulfur hexafluoride.

28. The method according to claim 24 wherein said monolayer comprises a phospholipid and said gaseous phase is perfluoropropane.

29. The method according to claim 1 wherein said vesicles comprise a polymer.

30. The method according to claim 29 wherein said polymer comprises an acrylate.

31. The method according to claim 30 wherein said gas is air.

32. The method according to claim 29 wherein said polymer comprises a methacrylate.

33. The method according to claim 32 wherein said gas is air.

34. The method according to claim 1 wherein said vesicles comprise a polysaccharide.

35. The method according to claim 34 wherein said polysaccharide comprises galactose.

36. The method according to claim 35 wherein said gaseous phase is nitrogen.

37. The method according to claim 15 wherein said aqueous suspension phase comprises liposomes.

38. The method according to claim 37 wherein said liposomes comprise cross-linked liposomes or polymerized liposomes.

39. The method according to claim 15 wherein said aqueous suspension phase further comprises polyethylene glycol.