Patient oxygenation using stabilized fluorocarbon emulsions

Abstract

Storage stable fluorocarbon emulsions having a continuous aqueous phase and a discontinuous fluorocarbon phase, in which the fluorocarbon phase comprises a major amount of a first fluorocarbon or fluorocarbon mixture, and a minor amount of a second fluorocarbon or fluorocarbon mixture, in which the second fluorocarbon has a molecular weight greater than that of the first fluorocarbon and the second fluorocarbon includes a lipophilic moiety in its structure, whereby the second fluorocarbon serves to promote particle size stability in the emulsion while simultaneously providing favorably short organ retention times when administered to animals in vivo.

1 . A stabilized fluorocarbon emulsion comprised of a continuous and discontinuous phase for use in in vivo oxygen transport, comprising: 
 a mixture of fluorocarbons comprising at least a first fluorocarbon from about 40-60% w/v of the emulsion and a second fluorocarbon from about 1-10% w/v of the emulsion; at least one emulsifying agent selected from the group consisting of lecithins, fluorinated surfactants and salts;    wherein the first and second fluorocarbons make up the discontinuous phase of the emulsion and the first fluorocarbon is comprised of a fluorocarbon having a molecular weight greater than 460 daltons and a second fluorocarbon having a molecular weight greater than about 540 daltons, wherein the first and second fluorocarbon each have at least one lipophilic moiety selected from the group consisting of Br, Cl and I; and the continuous phase is comprised of a pharmaceutically acceptable aqueous carrier.    
   
   
       2 . The stabilized fluorocarbon emulsion of  claim 1  wherein the stabilized emulsion is effective in transporting oxygen to the tissues throughout the body when the emulsion is saturated with oxygen and injected in vivo.  
   
   
       3 . The stabilized fluorocarbon emulsion of  claim 1  wherein the first fluorocarbon is selected from the group consisting of bis(F-alkyl) amines, cyclic fluorocarbons, C 7-12  perfluorinated amines, brominated fluorocarbons, perfluoroalkylated ethers, halogenated ethers and poly ethers all having a molecular weight greater than 460 daltons.  
   
   
       4 . The stabilized fluorocarbon emulsion of  claim 1  wherein the first fluorocarbon is a compound of the following general structure: 
 C n F 2n+1 R, wherein n is an integer from 6 to 8 and R comprises a lipophilic moiety selected from the group consisting of Br, Cl, I, CH 3  or a saturated or unsaturated hydrocarbon of 2 or 3 atoms.    
   
   
       5 . The stabilized flourocarbon emulsion of  claim 1  wherein the first fluorocarbon is perfluorooctyl bromide.  
   
   
       6 . The stabilized fluorocarbon emulsion of  claim 1  wherein the second fluorocarbon is a compound selected from the group of the following compounds: 
 a) C n F 2n+1 X, wherein n is 8 or greater, preferably 10 to 12, and X is a halide selected from the group consisting of Br, Cl or I;    b) C n F 2n X 2 , wherein n is 8 or greater, preferably 10 to 12, and X 2  is a halide selected from the group consisting of Br, CL or I; and,    c) Br—(C n F 2n+1 —O—C n′ F 2n′+1 ) wherein n and n′ are each at least 2 and the sum of n and n′ is greater or equal to 8.    
   
   
       7 . The stabilized fluorocarbon emulsion of  claim 1  wherein the second fluorocarbon is a compound selected from the group consisting of perfluorodecyl bromide, perfluoropolyether bromide and perfluorododecyl bromide.  
   
   
       8 . The stabilized fluorocarbon emulsion of  claim 1  wherein lecithin is an egg yolk phospholipid.  
   
   
       9 . The stabilized flouorocarbon emulsion of  claim 1  wherein the emulsion further comprises tocopherol.  
   
   
       10 . The stabilized fluorocarbon emulsion of  claim 1  wherein the emulsion further comprises NaCl.  
   
   
       11 . An emulsion for use in in vivo oxygen transport consisting of a continuous and discontinuous phase, wherein the discontinuous phase consists of two fluorocarbons, wherein the first fluorocarbon is selected from the group consisting of: 
 a) C n F 2n+1 X, wherein n is 8 or greater, preferably 10 to 12, and X is a halide selected from the group consisting of Br, Cl or I;    b) C n F 2n X 2 , wherein n is 8 or greater, preferably 10 to 12, and X 2  is a halide selected from the group consisting of Br, Cl or I;    c) Br—(C n F 2n+1 —O—C n′ F 2n′+1 ) wherein n and n′ are each at least 2 and the sum of n and n′ is greater or equal to 8;    d) C n F 2n+1 R—CH═CH-C n′ F 2n′+1 , wherein the sum of n and n′ equals 6 to 10; and,    e) C n F 2n+1 —O—C n′ F 2n′+1 , wherein the sum of n and n′ equals 6 to 10; and the second fluorocarbon is selected from the group consisting of perfluorodecyl bromide, perfluorododecyl bromide, 1-perfluorodecylethylene, 1-perfluorodecylethane, the continuous phase being comprised of a pharmaceutically acceptable aqueous carrier, and,    the emulsion further comprising an emulsifying agent.    
   
   
       12 . The emulsion of  claim 11  wherein the emulsifying agent is a phospholipid.  
   
   
       13 . The emulsion of  claim 11  wherein the emulsifying agent is a surfactant.  
   
   
       14 . The emulsion of  claim 11  wherein the first fluorocarbon is selected from the group consisting of: 
 C n F 2n+1 X, wherein n is 8 or greater, preferably 10 to 12, and X is a halide selected from the group consisting of Br, Cl or I; and,    C n F 2n X 2 , wherein n is 8 or greater, preferably 10 to 12, and X 2  is a halide selected from the group consisting of Br, Cl or I.    
   
   
       15 . The emulsion of  claim 11  wherein the second fluorocarbon is perfluorodecyl bromide.  
   
   
       16 . The emulsion of  claim 11  wherein the first fluorocarbon is perfluorooctyl bromide.  
   
   
       17 . An emulsion for use in in vivo oxygen transport comprising: 
 an aqueous continuous phase,    at least one emulsifying agent comprised of a phospholipid,    a discontinuous phase, comprising at least two fluorocarbons wherein the first fluorocarbon has a molecular weight greater than 460 daltons and the second fluorocarbon has a molecular weight greater than about 540 daltons, wherein the second fluorocarbon has at least one lipophilic moiety selected from the group consisting of Br, Cl, I and H; and    the continuous phase is comprised of a pharmaceutically acceptable aqueous carrier.    
   
   
       18 . The emulsion of  claim 17  wherein the first fluorocarbon is selected from the group consisting of bis(F-alkyl) amines, cyclic fluorocarbons, C 7-12  perfluorinated amines, brominated fluorocarbons, perfluoroalkylated ethers, halogenated ethers and poly ethers all having a molecular weight greater than 460 daltons.  
   
   
       19 . The emulsion of  claim 17  wherein the first fluorocarbon is selected from the group consisting of F-44E, F-i36E, perfluorodecalin, F-adamantane, perfluoroindane, F-methyladamantane, FDMA, perfluoro-2,2,4,4-tetramethylpentane, F-di-methylbicyclo[3,3,1]nonane, F-tri-methylbicyclo[3,3,1]nonane, F-tripropylamine, FMOQ, FMIQ, FHQ, FCHP, FC-75, RM11, perfluorooctyl bromide, 1-bromotridecafluorohexane, perfluorooctyl chloride and perfluorooctyl hydride.  
   
   
       20 . The emulsion of  claim 17  wherein the second fluorocarbon is selected from the group consisting of compounds having the following general structure: 
 a) C n F 2n+1 X, wherein n is 8 or greater, preferably 10 to 12, and X is a halide selected from the group consisting of Br, Cl or I;    b) C n F 2n X 2 , wherein n is 8 or greater, preferably 10 to 12, and X 2  is a halide selected from the group consisting of Br, CL or I; and,    c) Br—(C n F 2n+1 —O—C n′ F 2n′+1 ) wherein n and n′ are each at least 2 and the sum of n and n′ is greater or equal to 8.    
   
   
       21 . The emulsion of  claim 17  wherein the second fluorocarbon is selected from the group consisting of perfluorodecyl bromide, perfluorododecyl bromide, 1-perfluorodecylethylene, 1-perfluorodecylethane.