Activatable infusable dispersions containing drops of a superheated liquid for methods of therapy and diagnosis

• US 5,840,276 A
• Filed: 01/08/1997
• Issued: 11/24/1998
• Est. Priority Date: 01/11/1996
• Status: Expired due to Term

• Current Assignee: Apfel Enterprises, Inc.
• Original Assignee: Apfel Enterprises, Inc.
• Inventors: Apfel, Robert E.
• Primary Examiner(s): Hollinden, Gary E.
• Assistant Examiner(s): Hartley, Michael G.
• Application Number:
  US08/780,337
• Time in Patent Office: 685 Days
• Field of Search: 424/9.52, 424/9.5, 424/455, 424/9.3, 424/9.4, 548/422, 548/418, 548/407, 514/410, 514/937, 264/4.1, 427/213.3, 252/312, 252/314, 252/350, 600/458
• US Class Current: 424/9.52
• 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 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 9/0026 Blood substitute; Oxygen transporting formulations; Plasma extender

Abstract

Dispersions of superheated drops of immiscible liquids in aqueous continuous phase suitable for infusion into a human or other animal, the drops being vaporizable in a selected body location by ionizing radiation or ultrasound. The dispersions can be used to form diagnostic contrast agents, to improve diffusion of drugs, to occlude capillaries and to deliver drugs selectively in a localized body region.

Claims

1. A dispersion for therapeutic or diagnostic use comprising an aqueous continuous phase suitable for infusion into a human or other animal and dispersed drops comprising a practically immiscible superheated liquid, said drops having an average diameter of 0.05-20 μ

m, being physically stable in said composition and in said body and having an amount of superheat of at least 17 Celsius degrees, said amount of superheat being sufficient to permit their in-body nucleation by a level of ionizing radiation or ultrasound tolerable to said body.

2. The dispersion according to claim 1 wherein said superheated liquid comprises at least one component selected from the group consisting of fluorocarbons, chlorofluorocarbons, hydrocarbons and mixtures thereof.

3. The dispersion according to claim 1 wherein said superheated liquid has a boiling point at atmospheric pressure below -15°

C.

4. The dispersion according to claim 1 further comprising a gelling or thickening agent.

5. The dispersion according to claim 1 wherein said drops further comprise at least one drug that is releasable by nucleation of said drops.

6. The dispersion according to claim 5 wherein said superheated liquid has a boiling point at atmospheric pressure below -15°

C.

7. The dispersion according to claim 6 further comprising an emulsifier.

8. The dispersion according to claim 6 wherein said superheated liquid comprises at least one component selected from the group consisting of fluorocarbons, chlorofluorocarbons, hydrocarbons and mixtures thereof.

9. The dispersion according to claim 5 wherein said superheated liquid includes a solvent for said at least one drug.

10. The dispersion according to claim 9 further comprising an emulsifier.

11. The dispersion according to claim 5 wherein said at least one drug is selected from the group consisting of radiation sensitizers and bioreductive alkylating agents.

12. The dispersion according to claim 1 wherein said aqueous phase comprises an intravenous solution.

13. The dispersion according to claim 1 further comprising an emulsifier.

14. A method of delivering at least one drug to a selected body location comprising the steps of:

a) infusing a dispersion according to claim 5; and

b) selectively subjecting said body location to energy from the group consisting of ionizing radiation and ultrasound to vaporize the drops of said dispersion, thereby releasing said drug at said body location.

15. The method according to claim 14, wherein said energy is ionizing radiation.

16. The method according to claim 15, wherein said energy is produced by a radiation source implanted in said body at or near said selected body location.

17. The method according to claim 14 wherein said dispersion contains an emulsifier.

18. The method according to claim 14 wherein the superheated liquid in said dispersion has a boiling point at atmospheric pressure below -15°

C.

19. The method according to claim 14 wherein said step of infusing comprises injecting intravenously.

20. The method according to claim 19 wherein said energy is ionizing radiation.

21. The method according to claim 19 wherein said superheated liquid comprises at least one component selected from the group consisting of fluorocarbons, chlorofluorocarbons, hydrocarbons and mixtures thereof.

22. The method according to claim 14 wherein said dispersion is an emulsion, wherein said superheated liquid comprises at least one component selected from the group consisting of fluorocarbons, chlorofluorocarbons, hydrocarbons and mixtures thereof, and wherein said superheated liquid has a boiling point at atmospheric pressure in the range of below -15°

C.

23. The method according to claim 22 wherein said superheated liquid includes a solvent for said at least one drug.

24. The method according to claim 14 further comprising the step of stimulating vaporized drops with ultrasound to impart motion thereto sufficient to increase diffusion of said at least one drug.

25. The method according to claim 14, further comprising the step of monitoring said infusion and vaporization by diagnostic imaging of said selected body location using bubbles formed by said vaporization as contrast agents.

26. In the process of diagnostically imaging a selected body location, the improvement comprising injecting intravenously a dispersion according to claim 1 and subjecting said body location to ionizing radiation or ultrasound to vaporize the drops of said dispersion, thereby producing at said location bubbles which serve as contrast agents.

27. The method according to claim 14, wherein said at least one drug is selected from the group consisting of radiation sensitizers and bioreductive alkylating agents.

28. A method of delivering gaseous bubbles to a selected body location comprising the steps of infusing a dispersion according to claim 1 and selectively subjecting said body location to energy selected from the group consisting of ionizing radiation and ultrasound to vaporize the drops of said dispersion.

29. The method according to claim 28 wherein said step of infusing comprises intravenous injection, wherein said selected body location includes capillaries, and wherein vaporization of said drops occludes said capillaries.

30. The method according to claim 29 wherein said dispersion includes an emulsifier.

31. The method according to claim 28 wherein a drug is delivered to said selected body location, further comprising the step of stimulating vaporized drops with ultrasound to impart motion thereto sufficient to increase diffusion of said drug.