Emulsion stability

Abstract

An injectable physiologically acceptable aqueous phase fluorocarbon emulsion, which has substantially no free fluorocarbon, has an excellent stability is prepared by a process of the invention. Typically, more than about 99.8 wt. % of the fluorocarbon remains in the size range of about 0.2 to 0.4 microns even after being stored at room temperature for one year or more in sealed containers under a non-oxidizing atmosphere. The emulsion is useful in medical applications, for example, coronary angioplasty, cancer therapy, among others.

The following is claimed:  
     
       1. A method for making a stable emulsion having substantially completely no unemulsified fluorocarbon comprising the steps of: 
       preparing an aqueous electrolyte solution,  
       preparing a dispersion by introducing at least one emulsifying agent into the solution,  
       admixing at least one perfluorocarbon into the dispersion to form an emulsion,  
       applying an interior coating comprising silicone oil or lecithin to a storage container,  
       storing the emulsion in the container which has a non-oxidizing atmosphere, wherein said emulsion contains substantially completely no unemulsified perfluorocarbon, and;  
       optionally agitating the emulsion.  
     
     
       2. The method of  claim 1  wherein said perfluorocarbon comprises at least one of perfluoroocytl bromide and bisperfluorobutyl ethylene. 
     
     
       3. The method of  claim 1  wherein said electrolyte comprises at least one member from the group consisting of sodium chloride, potassium chloride, dibasic sodium phosphate, sodium bicarbonate, hydrated sodium citrate, hydrated calcium chloride, and hydrated magnesium chloride. 
     
     
       4. The method of  claim 1  wherein said emulsifying agent comprises egg yolk lecithin. 
     
     
       5. The method of  claim 1  further comprising sterilizing the stored emulsion. 
     
     
       6. The method of  claim 1  further comprising purging at least one of the electrolyte solution and the perfluorocarbon with carbon dioxide. 
     
     
       7. The method of  claim 1  further comprising depyrogenating said coated container. 
     
     
       8. The method of  claim 7  wherein said depyrogenating comprises heating said coated container to about 250° C. 
     
     
       9. A method for making a stabilized fluorocarbon emulsion comprising: 
       providing a fluorocarbon emulsion which comprises a fluorocarbon, an emulsifying agent and an aqueous medium; and  
       storing the emulsion in a container which has been coated with a composition comprising silicone oil or lecithin, wherein the stored emulsion is substantially free of unemulsified fluorocarbon.  
     
     
       10. A stable emulsion comprising about 10 to about 50% volume/volume (v/v) of a liquid perfluorocarbon which has a molecular weight in the range of about 460-520, about 1-8% weight/volume (w/v) of an emulsifying agent, and the balance comprising a physiologically acceptable saline solution; wherein said emulsion contains substantially no unemulsified fluorocarbon and is stored in a container, the interior of which has been coated with a composition comprising silicone oil or lecithin. 
     
     
       11. The emulsion of  claim 10  which is prepared by admixing together said perfluorocarbon, emulsifying agent and saline solution and storing said admixture in said container. 
     
     
       12. The emulsion of  claim 10  wherein said coated container is also depyrogenated. 
     
     
       13. The emulsion of  claim 12  wherein said coated container is depyrogenated by heating to about 250° C. 
     
     
       14. A container containing a physiologically acceptable sterile fluorocarbon emulsion including an emulsifying agent, 
       
         wherein the container has on the inside surface a polymer or firmly bound monolayer which reduces interaction between the container and the emulsion,  
       
       
         wherein the quantity of unemulsified fluorocarbon is minimal as measured by an increase in the average emulsion droplet size to less than about  0 . 60  microns when the fluorocarbon emulsion is stored about  24 ° C. for one year in a sealed container, and  
       
         the unemulsified fluorocarbon can be substantially completely re - emulsified by agitating or shaking the container.   
     
     
       15. The container of  claim 14  wherein the container has a capacity of  100  ml or greater. 
     
     
       16. The container of  claim 15  wherein the container is an infusion bottle. 
     
     
       17. The container of  claim 14  wherein the fluorocarbon emulsion is stable when stored under ambient conditions when the container is sealed for a year or more without significant deterioration, as evidenced by an average emulsion droplet size increase of less than about  0 . 60  microns. 
     
     
       18. The container of  claim 14 , wherein the fluorocarbon emulsion is stable when stored for more than two years at a temperature of about  4 ° C. 
     
     
       19. The container of  claim 14  wherein the fluorocarbon emulsion comprises between about  10  through  50 %  volume/volume of at least one liquid perfluorocarbon which as a molecular weight in the range of about  460 - 520 , between about one and eight  %  weight/volume of at least one emulsifying agent, and the balance comprising a physiologically acceptable saline solution.