Brominated perfluorocarbon emulsions for internal animal use for contrast enhancement and oxygen transport

• US 4,865,836 A
• Filed: 01/14/1986
• Issued: 09/12/1989
• Est. Priority Date: 01/14/1986
• Status: Expired due to Term

• Current Assignee: PFC Therapeutics, LLC
• Original Assignee: Fluoromed Pharmaceutical, Inc. (Alliance Pharmaceutical Corporation)
• Inventors: Long, David M. Jr.
• Primary Examiner(s): WADDELL, FREDERICK
• Application Number:
  US06/818,690
• Time in Patent Office: 1,337 Days
• Field of Search: 514/832, 514/772, 424/5
• US Class Current: 424/9.4
• 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 977/915 Therapeutic or pharmaceutical composition
• CPC Class Codes: Y10S 977/927 Diagnostic contrast agent

Abstract

A brominated perfluorocarbon emulsion non-toxic for internal and intravenous use in animals including humans for use as an oxygen transport medium and as a tumor and other element contrast enhancement medium is stable with very small size characteristics for extended periods in excess of eighteen months and after sterilization, with a stabilizing component selected from the class comprising steroid hormones, tocopherols, cholesterols and their combinations. An anti-oxidizing component enhances delivery in oxygen transport.

Claims

1. A process for preparing a brominated perfluorocarbon emulsion capable of carrying oxygen to animal tissues having size stability characteristics for an extended period of time and resistant to attack by animal organisms in animal body fluids, comprising the steps of:

a. dispersing purified phospholipid emulsifier in a buffered aqueous solution containing an osmotic agent, and a biocompatible amount of a compound selected from the group consisting of sterols, tocopherols and combinations thereof;

b. gradually mixing into said dispersed emulsifier and solution from about 55% to about 125% weight per volume of brominated perfluorocarbon; and

,

c. directing said mixture through a emulsification apparatus having fluid velocities of at least 1500 feet per second under such high shear conditions as to form a stable, heat-sterilizable emulsion, wherein the amount of emulsifier in said emulsion is an effective amount and the amount of osmotic agent and the buffer are effective to approximate physiological biocompatible osmolarity and pH.

2. A process for preparing a brominated perfluorocarbon emulsion capable of carrying oxygen to animal tissues having size stability characteristics for an extended period of time, comprising the steps of:

a. dispersing purified emulsifier in a buffered aqueous solution of an osmotic agent;

b. mixing from about 55% to 125% weight per volume of brominated perfluorocarbon into said dispersion of emulsifier and solution; and

,

c. passing the resulting mixture through an emulsifying apparatus generating such high shear conditions as to form a stable, heat-sterilizable emulsion, wherein the amounts of buffer and osmotic agent in said emulsion are effective to approximate physiological pH and osmolarity.

3. The process of claim 2, wherein said passing step further comprises passing the resulting mixture through said emulsifying apparatus a plurality of times in a plurality of flows in separate flow paths and redirecting said plurality of flows into each other at least 4,000 pounds per square inch of pressure.

4. The process of claim 2 wherein in said passing step, said mixture is flowing at velocities in excess of 1500 feet per second.

5. A process for preparing a fluorocarbon emulsion capable of carrying oxygen to animal tissues, said emulsion having substantial particle size stability characteristics for an extended period of time and through heat sterilization, comprising the steps of:

a. mixing an effective amount of an emulsifier in an aqueous phase;

b. mixing of from about 55% to 125% weight per volume of a non-toxic fluorocarbon into said mixture of emulsifier and aqueous phase; and

c. passing the fluorocarbon-containing mixture through a mechanical emulsifying apparatus having a flow path, in which said mixture is subjected to sufficiently high shear rates to form a stable, heat sterilizable emulsion.

6. The process of claim 5 wherein said passing step is repeated.

7. The process of claim 6 wherein said passing step is repeated at least four times.

8. The process of claim 5 wherein in said passing step, said flow is maintained at approximately 1500 feet per second velocity.

16. The process of claim 5, wherein said fluorocarbon-containing mixture is subjected to a pressure of at least 4000 pounds per square inch in said emulsifying apparatus.

17. The process of claim 5, wherein said fluorocarbon-containing mixture is subjected to flow rates of at least 1500 feet per second in said emulsifying apparatus.

9. A process for preparing a fluorocarbon emulsion having particle size stability characteristics for an extended period of time, comprising the steps of:

a. mixing an effective amount of emulsifier and from about 55% weight per volume to 125% weight per volume of a biocompatible fluorocarbon into an aqueous phase to form a mixture; and

,

b. placing said mixture in an emulsification apparatus and pressurizing said mixture at a pressure of at least 4000 pounds per square inch to force said mixture through at least one high shear emulsification flow path at a velocity of at least 1500 feet per second.

10. The process of claim 9 wherein in said pressurizing step, said mixture is forced into a plurality of flow paths which direct the mixture flows to impinge against each other in an impingement cavity.

11. The process of claim 9 wherein said mixing step, the fluorocarbon is mixed into said aqueous phase after said emulsifier is mixed into said aqueous phase.

12. The process of claim 11 wherein said fluorocarbon is mixed into said aqueous phase in said at least one flow path.

13. The process of claim 11 wherein in said mixing step, a buffering agent is mixed into said aqueous phase.

14. The process of claim 11 wherein in said mixing step, an osmotic agent is mixed into said aqueous phase.

15. The process of claim 9 wherein said fluorocarbon is a brominated fluorocarbon.

18. A process for preparing a fluorocarbon emulsion capable of carrying oxygen to animal tissues, said emulsion having substantial particle size stability characteristics for an extended period of time though heat sterilization, comprising the steps of:

combining an aqueous phase with an effective amount of an emulsifier and from about 50% to about 125% weight per volume of a fluorocarbon to form a mixture; 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 emulsion.

19. The process of claim 18, wherein said fluorocarbon is brominated.

20. The process of claim 18, wherein said mixture is subjected to a pressure of at least 4000 pounds per square inch in said emulsifying apparatus.

21. The process of claim 18, wherein said mixture is subjected to flow rates of at least 1500 feet per second.

22. The process of claim 18, wherein said mixture contains from about 80% to about 125% weight per volume of said fluorocarbon.