Therapeutic delivery systems related applications

• US 5,542,935 A
• Filed: 11/30/1993
• Issued: 08/06/1996
• 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): JAWORSKI, FRANCIS J
• Application Number:
  US08/160,232
• Time in Patent Office: 980 Days
• Field of Search: 128/662.02, 264/4.3, 264/4.5, 604/190, 260/309.6, 261/128, 366/101, 428/402, 428/402.2, 424/450
• US Class Current: 604/190
• 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 47/6911 the form being a liposome
• CPC Class Codes: A61K 47/6925 the form being a microcapsule, nanocapsule, microbubble or nanobubble
• 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 977/904 for medical, immunological, body treatment, or diagnosis
• CPC Class Codes: Y10S 977/907 Liposome

Abstract

Therapeutic delivery systems comprising gaseous precursor-filled microspheres comprising a therapeutic are described. Methods for employing such microspheres in therapeutic delivery applications are also provided. Therapeutic delivery systems comprising gaseous precursor-filled liposomes having encapsulated therein a contrast agent or drug are preferred. Methods of and apparatus for preparing such liposomes and methods for employing such liposomes in therapeutic delivery applications are also disclosed.

Claims

1. An apparatus for making therapeutic containing liposomes filled with a gaseous precursor, comprising:

a) a vessel;

b) means for introducing an aqueous solution comprising a lipid and a therapeutic compound into said vessel;

c) means for introducing a gaseous precursor into said vessel;

d) means for instilling said gaseous precursor into said aqueous solution in said vessel; and

e) cooling means for cooling said aqueous solution below the gel to liquid crystalline phase transition temperature of said lipid in said aqueous solution and for maintaining said gaseous precursor in said vessel at a temperature below its liquid to gas phrase transition temperature during said instillation of said gaseous precursor into said aqueous solution, thereby producing a foam containing gaseous precursor-filled liposomes within said vessel.

2. The apparatus according to claim 1, wherein said means for introducing an aqueous lipid solution comprises means for introducing dried lipids, means for introducing a therapeutic compound, and means for introducing an aqueous media into said vessel.

3. The apparatus according to claim 1, wherein said means for instilling said gaseous precursor into said aqueous solution comprises means for shaking said aqueous solution.

4. The apparatus according to claim 3, wherein said means for shaking said aqueous solution comprises means for shaking said vessel.

5. The apparatus according to claim 3, wherein said means for shaking said aqueous solution comprises means for vortexing said aqueous solution.

6. The apparatus according to claim 1, further comprising means for extracting said foam from said vessel.

7. The apparatus of claim 6 wherein said vessel is a barrel of a syringe, said syringe also comprising a needle and a filter, said filter disposed between said barrel and said needle;

said means for extracting comprises means for extruding said gas-filled liposomes from said barrel through said filter, thereby sizing said liposomes.

8. The apparatus of claim 6 wherein said vessel is a barrel of a syringe.

9. The apparatus of claim 8 wherein said syringe comprises a barrel, a filter, and a needle;

said means for extracting comprises means for sizing said gas-filled liposomes by extruding said liposomes from said barrel through said filter.

10. The apparatus of claim 6 wherein said vessel is a barrel of a syringe, said syringe also comprising a needle and means for sizing said liposomes upon extruding said liposomes from said barrel, said sizing means including a filter.

11. The apparatus of claim 10 wherein said filter is a first filter and further comprising a second filter, said first filter and said second filter having pores, said second filter having a pore size of about 10 μ

m and said first filter having a pore size of about 8 μ

m.

12. The apparatus of claim 10, wherein said filter has pores, said pores having a size in the range of about 30 nm to about 20 microns.

13. The apparatus of claim 10, wherein said filter has pores, said pores having a size of about 8 μ

m.

14. The apparatus of claim 10, wherein said filter having pores, said pores having a size of about 0.22 μ

m.

15. The apparatus of claim 6 wherein said means for extracting comprises means for drawing said gas-filled liposome-containing foam into a syringe, said syringe comprising a barrel, a filter, and a needle;

whereby said liposomes are sized upon extraction.

16. The apparatus of claim 15, wherein said filter is a first filter and further comprising a second filter, said first and second filters each having pores, said second filter having a pore size of about 10 μ

m and said first filter having a pore size of about 8 μ

m.

17. The apparatus of claim 15 wherein said filter is a first filter and further comprising a second filter, wherein said first and second filters each have pores, said pores having a size in the range of about 30 nm to about 20 microns.

18. The apparatus of claim 15, wherein said filter has pores, said pores having a size of about 8 μ

m.

19. The apparatus of claim 15, wherein said filter having pores, said pores having a size of about 0.22 μ

m.

20. The apparatus according to claim 1, further comprising means for sizing said gaseous precursor-filled liposomes.

21. The apparatus according to claim 1, further comprising a filter in flow communication with said vessel.

22. The apparatus according to claim 1, further comprising means for pressurizing said vessel.

23. The apparatus according to claim 1, further comprising means for flowing said gaseous precursor-filled liposomes produced from said vessel into a syringe substantially without further processing.

24. The apparatus of claim 1 further comprising a means for regulating temperature.

25. The apparatus of claim 24 wherein said temperature is regulated to 37°

C.

26. The apparatus of claim 1 wherein said vessel is a barrel of a syringe, said syringe also comprising a needle and means for sizing said liposomes upon drawing said liposomes into said barrel, said sizing means including a filter.

27. The apparatus of claim 1, wherein said cooling means has means for cooling said gaseous precursor to a temperature less than about 37°

C.

28. An apparatus for making therapeutic containing gas-filled liposomes, comprising:

a) a vessel;

b) means for introducing an aqueous solution comprising a lipid and a therapeutic compound into said vessel;

c) means for introducing a gaseous precursor into said vessel;

d) means for instilling said gaseous precursor into said aqueous solution in said vessel, thereby producing a foam containing gaseous precursor-filled liposomes within said vessel; and

e) means for extracting said foam from said vessel, said means for extracting said foam from said vessel having means for adjusting the vertical location at which said foam is extracted from said vessel so as to regulate the size of said liposomes extracted.

29. The apparatus according to claim 28, further comprising means for flowing said gaseous precursor-filled liposomes extracted by said extracting means through a filter assembly.

30. The apparatus according to claim 29, wherein said filter assembly comprises first and second filters spaced a predetermined distance apart.

31. The apparatus according to claim 30, further comprising means for pressurizing said vessel.

32. The apparatus of claim 30, wherein said extraction means comprises:

a) a tube; and

b) means for vertically displacing said tube within said vessel.

33. An apparatus for making therapeutic containing gas-filled liposomes, comprising:

a) a vessel;

b) means for introducing an aqueous solution comprising a lipid and a therapeutic compound into said vessel;

c) means for introducing a gaseous precursor into said vessel;

d) means for instilling said gaseous precursor into said aqueous solution in said vessel, thereby producing a foam containing gaseous precursor-filled liposomes within said vessel; and

e) means for sizing said liposomes, said sizing means including a syringe having (i) a barrel portion for receiving said liposomes, (ii) a needle portion, (iii) a filter disposed between said barrel and said needle, and (iv) a plunger for extruding said liposomes through said filter.

34. The apparatus according to claim 33, wherein said syringe forms means for extracting said foam from said vessel, whereby said liposomes are sized as they are extracted from said vessel.

35. An apparatus for making therapeutic containing gas-filled liposomes, comprising:

a) means for instilling a gaseous precursor into an aqueous solution comprising a lipid and a therapeutic compound, thereby forming a foam containing gaseous precursor-filled liposomes;

b) means for sizing said liposomes, said sizing means including a syringe having (i) a barrel portion, said barrel portion of said syringe forming a vessel in which said liposomes are formed, (ii) a needle portion, (iii) a filter disposed between said barrel and said needle, and (iv) a plunger for extruding said liposomes through said filter, whereby said liposomes are sized as they are injected into a patient;

c) means for introducing said gaseous precursor into said barrel portion of said syringe; and

d) means for introducing said aqueous solution into said barrel portion of said syringe.

36. An apparatus for making gaseous precursor filled liposomes coated with a therapeutic, comprising:

a) a vessel;

b) means for sequentially introducing an aqueous solution comprising a lipid into said vessel and then introducing a therapeutic compound into said vessel;

c) means for introducing a gaseous precursor into said vessel prior to said introduction of said therapeutic compound; and

d) means for instilling said gaseous precursor into said aqueous solution in said vessel prior to said introduction of said therapeutic compound, thereby forming gaseous precursor filled liposomes;

whereby said therapeutic compound introducing means introduces said therapeutic compound into said vessel after said formation of said gaseous precursor filled liposomes so that said therapeutic compound coats said gaseous precursor filled liposomes.