Microbubbles and methods for oxygen delivery

Abstract

Compositions containing a carrier and microbubles encapsulating one or more gases, preferably oxygen, and methods for making and using the compositions are described herein. The microbubbles contain a lipid envelope formed of at least one base lipid and at least one emulsifying agent. The compositions may be administered to a patient to quickly deliver large amounts of oxygen to the patient's blood supply or directly to a tissue in need of oxygen. The compositions may be administered via injection or as a continuous infusion. The compositions contain a concentrated microbubble suspension, where the suspension contains at least 40 mL oxygen/dL suspension. The microbubbles are preferably less than 20 microns in diameter, more preferably less than 15 microns in diameter. The microbubbles described herein may be administered to a patient in an effective amount to increase in oxygen concentration in the patient's blood, and/or one or more tissues or organs. The microbubbles may be administered alone or in combination with other treatments as an adjuctive therapy.

1 . A method for delivering oxygen to a patient, tissue or organ, comprising
 administering to the patient, tissue or organ a composition, comprising a suspension comprising microbubbles and a carrier, wherein the microbubbles comprise a lipid envelope and a gas core, wherein the gas core comprises oxygen, wherein the lipid envelope comprises one or more lipids in the form of a lipid film, and one or more emulsifying agents, wherein the outer surface of the lipid film forms a protective border, wherein the one or more emulsifying agents comprises a group or molecule that forms the protective border, and wherein the suspension comprises at least 40% oxygen by volume,   wherein the composition is administered in an effective amount to increase the concentration of oxygen in the patient's blood, tissue or organ in need of oxygen.   
   
   
       2 . The method of  claim 1 , wherein the protective border comprises polyethylene glycol. 
   
   
       3 . The method of  claim 1 , wherein the lipid film is a monolayer. 
   
   
       4 . The method of  claim 3 , wherein the lipid envelope comprises at least one base lipid and wherein the one or more emulsifying agents comprise a PEGylated lipid. 
   
   
       5 . The method of  claim 1 , wherein the oxygen is administered via injection or as a continuous infusion. 
   
   
       6 . The method of  claim 1 , wherein the patient in need of treatment is experiencing local or systemic hypoxia. 
   
   
       7 . The method of  claim 6 , wherein the hypoxic conditions arise in the patient as a result of a disease or disorder selected from the group consisting of congenital physical or physiologic diseases or disorders, embolisms, peripheral artery occlusive disease, transient ischemic attacks, strokes, acute trauma, surgical interventions, and exposure to chemical or environmental agents. 
   
   
       8 . The method of  claim 1 , wherein the suspension comprises 40 to 70% oxygen by volume. 
   
   
       9 . The methods of  claim 1 , wherein the composition is administered at a rate of 0.5 to 400 mL/minute. 
   
   
       10 . A method for forming a concentrated microbubble suspension comprising
 (a) forming a microbubble suspension comprising a lipid envelope and a gas core, wherein the gas core comprises oxygen, wherein the lipid envelope comprises one or more lipids in the form of a lipid film and one or more emulsifying agents, wherein the outer surface of the lipid film forms a protective border, wherein the one or more emulsifying agents comprises a group or molecule that forms the protective border,   (b) centrifuging the microbubble suspension, and   (c) separating the microbubbles based on size to form a concentration microbubble suspension.   
   
   
       11 . The method of  claim 10 , wherein the concentrated microbubble suspension contains at least four times the volume of oxygen that was present in the microbubble suspension formed in step (a). 
   
   
       12 . The method of  claim 10 , wherein the microbubbles in the concentrated microbubble suspension have diameters of 20 microns or less. 
   
   
       13 . A composition for rapidly delivering oxygen to a patient in need thereof comprising a suspension comprising microbubbles and a carrier, wherein the microbubbles comprise a lipid envelope and a gas core, wherein the gas core comprises oxygen, wherein the lipid envelope comprises one or more lipids in the form of a lipid film and one or more emulsifying agents, wherein the outer surface of the lipid film forms a protective border, wherein the one or more emulsifying agents comprises a group or molecule that forms the protective border, and wherein the suspension comprises at least 40% oxygen by volume. 
   
   
       14 . The composition of  claim 13 , wherein the protective border comprises polyethylene glycol. 
   
   
       15 . The composition of  claim 13 , wherein the lipid envelope comprises at least one base lipid and wherein the one or more emulsifying agents comprise a PEGylated lipid. 
   
   
       16 . The composition of  claim 13 , wherein carrier is suitable for injection. 
   
   
       17 . The composition of  claim 15 , wherein base lipid is a phospholipid comprising acyl chains of less than 24 carbons. 
   
   
       18 . A kit for rapidly delivering oxygen to a patient in need thereof comprising
 (a) one or more lipids and one or more emulsifying agent for forming microbubbles,   (b) a pharmaceutically acceptable carrier, and   (c) a source of oxygen,   wherein when (a), (b), and (c) are combined to form a microbubble suspension, the microbubbles comprise a lipid envelope and a gas core, wherein the gas core comprises oxygen, wherein the lipid envelope comprises one or more lipids in the form of a lipid film and one or more emulsifying agents, wherein the outer surface of the lipid film forms a protective border, wherein the one or more emulsifying agents comprises a group or molecule that forms the protective border, and wherein the suspension comprises at least 40% oxygen by volume.   
   
   
       19 . The kit of  claim 18  comprising instructions for forming the microbubbles and administering the microbubbles to a patient, tissue or organ in need thereof. 
   
   
       20 . The kit of  claim 19  in a sterile packaging. 
   
   
       21 . A system for rapidly delivering oxygen to a patient in need thereof comprising
 (a) a means for generating a suspension comprising microbubbles and a carrier, wherein the microbubbles comprise a lipid envelope and a gas core, wherein the gas core comprises oxygen, wherein the lipid envelope comprises one or more lipids in the form of a lipid film and one or more emulsifying agents, wherein the outer surface of the lipid film forms a protective border, wherein the one or more emulsifying agents comprises a group or molecule that forms the protective border, and wherein the suspension comprises at least 40% oxygen by volume, and   (b) means for administering microbubbles continuously or discontinuously to a patient, tissue or organ in need thereof.   
   
   
       22 . A method for delivering one or more gases to a patient, comprising administering to the patient a composition, comprising a suspension comprising microbubbles and a carrier, wherein the microbubles comprise a lipid envelope and a gas core, wherein the gas core comprises at least one gas, wherein the gas is not a fluorinated gas, wherein the lipid envelope comprises one or more lipids in the form of a lipid film, and one or more emulsifying agents, wherein the outer surface of the lipid film forms a protective border, wherein the one or more emulsifying agents comprises a group or molecule that forms the protective border, and wherein the suspension comprises at least 40% of the one or more gases by volume,
 wherein the composition is administered in an effective amount to increase the concentration of the one or more gases in the patient's blood, tissue or organ.