Method for preparing storage stable colloids

• US 5,595,723 A
• Filed: 11/08/1993
• Issued: 01/21/1997
• Est. Priority Date: 01/25/1993
• Status: Expired due to Fees

• Current Assignee: GE Healthcare As (GE Healthcare Technologies, Inc.)
• Original Assignee: Sonus Pharmaceuticals Inc. (Achieve Life Sciences, Inc.)
• Inventors: Quay, Steven C.
• Primary Examiner(s): Prior, Kimberly J.
• Assistant Examiner(s): TILL, MARY C
• Application Number:
  US08/148,284
• Time in Patent Office: 1,170 Days
• Field of Search: 424/9, 424/450, 424/9.5, 424/9.51, 424/9.52, 128/662.02
• US Class Current: 424/9.5
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 49/226 Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels

Abstract

Agents for enhancing the contrast in a diagnostic ultrasound procedure comprise colloidal dispersions of the liquid-in-liquid type, i.e., emulsions or microemulsions, in which the dispersed liquid phase is a high vapor pressure chemical which undergoes a phase change from a dispersed liquid to a highly echogenic dispersed gaseous foam or kugelschaum following administration to an organism. The liquid state of the dispersed phase allows one to manufacture extremely stable, pharmaceutically acceptable emulsions with particle sizes typically below 1000 nm. The gaseous state at body temperature yields highly echogenic microbubbles, typically below 10,000 nm in diameter, which are effective as ultrasound contrast agents. Intravenous, intraarterial, oral, intraperitoneal, and intrauterine dosage forms, methods of administration, and imaging techniques are described.

Claims

1. A method of preparing a storage stable ultrasound contrast agent comprising the steps of:

(a) mixing at least one amphiphilic material with water to form an aqueous continuous phase;

(b) adding an amount of a fluorine-containing compound in gas form which has a boiling point less than 37°

C. to said continuous phase; and

(c) condensing said gas to form a liquid in liquid colloidal dispersion having dispersed phase particles with an average diameter of less than 5000 nm.

2. The method of claim 1 wherein said liquid is selected from the group consisting of aliphatic hydrocarbons, organic halides, or ethers having six or fewer carbon atoms.

3. The method of claim 1 wherein said compound is selected from the group consisting of decafluorobutane, dodecafluoropentane, dodecafluoroneopentane and perfluorocyclopentane.

4. The method of claim 1 wherein said amphiphilic material comprises a biocompatible protein.

5. The method of claim 1 wherein said amphiphilic material comprises at least one surfactant.

6. The method of claim 4 wherein said protein is selected from the group consisting of albumin, fibrinogen, fibrin, serum globulins, hemoglobin, myoglobin, and immunoglobulins.

7. The method of claim 1 wherein said amphiphilic material comprises a polyoxypropylene-polyoxyethylene glycol nonionic block copolymer.

8. The method of claim 1 wherein said amphiphilic material comprises a fluorine-containing surfactant.

9. The method of claim 1 wherein said amphiphilic material is selected from the group of surfactants consisting of anionic, cationic, nonionic, or zwitterionic molecules.

10. The method of claim 1 wherein said amphiphilic material comprises at least one surfactant selected from the group of surfactants which contain, as hydrophilic groups, one or more of the following chemical groups:

sulfonate, sulfate, carbonylate, phosphate, ammonium, quaternary ammonium, betaines, sulfobetaines, polyoxyethylene, polyols, alcohols, ethers, polypeptide, or polyglycidyl; and

as hydrophobic groups, one or more of the following chemical groups;

fatty acids, paraffins, olefins, alkyl benzenes, alcohols, alkylphenols, polyoxypropylenes, polypeptides, fluorocarbons and silicones.

11. The method of claim 1 wherein said amphiphilic material is added to said aqueous continuous phase in an amount such that it is present at a concentration between 0.001% and 6.0% by weight per volume therein.

12. The method of claim 1 further comprising the step of adding of a viscogen to said continuous phase.

13. The method of claim 12 wherein said viscogen is selected from the group consisting of glucose, iohexol, iopamidol, iopentol, sorbitol, sucrose, and polyethylene glycol.

14. The method of claim 13 wherein the viscogen is present at a concentration sufficient to produce a viscosity greater than 1.1 cP.

15. The method of claim 13 wherein the viscogen is present at a concentration of between 0.001 and 75% by weight per volume.

16. The method of claim 1 wherein the diameter of the particles is less than 1000 nm.

17. The method of claim 1 wherein the concentration of said liquid dispersed phase is between 0.00001 to 166% by weight per volume.

18. The method of claim 1 comprising the further step of adding an additive selected from the group of acidifying agents, alkalizing agents, antimicrobial preservatives, antioxidants, buffering agents, chelating agents, complexing agents, solubilizing agents, humectants, solvents, suspending agents, viscosity-increasing agents and tonicity agents to said continuous phase.

19. The method of claim 18 wherein said additive is present at a concentration such that the osmolarity of said continuous phase is at least 250 mOm.

20. The method of claim 1 wherein said compound comprises a chemical selected from the group of chemicals containing 4 to 17 atoms.

21. The method of claim 1 where said compound has a vapor pressure of greater than 20 mm Hg at ambient temperature.

22. The method of claim 1 wherein said fluorine containing compound is selected from the group consisting of aliphatic hydrocarbons, organic halides, or ethers having six or fewer carbons.

23. The method of claim 1 consisting of the steps (a)-(c).

24. A method of preparing a storage stable ultrasound contrast agent comprising the steps of:

(a) mixing a surfactant with water to form an aqueous continuous phase;

(b) adding a fluorine-containing compound in gas form to said aqueous continuous phase, said compound having a boiling point less than 37°

C.; and

(c) forming a liquid in liquid colloidal dispersion by condensing said gas in said aqueous continuous phase to form dispersed phase particles with an average diameter less than 5000 nm.

25. A method of preparing a storage stable ultrasound contrast agent comprising the steps of:

(a) mixing a surfactant with water to form an aqueous continuous phase;

(b) adding a fluorine-containing compound in gas form to said aqueous continuous phase, said compound having a boiling point less than 37°

C. and being selected from the group consisting of aliphatic hydrocarbons, organic halides and ethers having six or fewer carbon atoms; and

(c) forming a liquid in liquid colloidal dispersion by condensing said gas in said aqueous continuous phase.

26. A method of preparing a storage stable ultrasound contrast agent comprising the steps of:

(a) mixing at least one amphiphilic material with water;

(b) adding a fluorocarbon gas to the mixture; and

(c) forming a liquid in liquid colloidal dispersion by condensing said gas to form a liquid dispersed phase containing said fluorocarbon.

27. The method of claim 26 wherein said fluorocarbon is selected from the group consisting of perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane and mixtures thereof.

28. The method of claim 27 wherein said fluorocarbon is perfluoropentane.

29. A method of preparing a storage stable ultrasound contrast agent including a liquid in liquid colloidal dispersion comprising the steps of:

(a) adding at least one amphiphilic material to water to form a mixture; and

(b) condensing a fluorine-containing compound in gaseous form which has a boiling point below 37°

C. into said mixture.

30. The method of claim 29 wherein said fluorine-containing compound is selected from the group consisting of perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane and mixtures thereof.

31. The method of claim 30 wherein said fluorine-containing compound is perfluoropentane.