Method of preserving oxygen infusions
The present invention provides a method for preserving an oxygen infusion containing an aqueous suspension of molecular assemblies which contain hemoglobin or a heme compound, by: a) modifying the molecular assemblies with polyoxyethylene; and b) converting the hemoglobin or the heme compound into a deoxy-form by removing oxygen from the suspension.
1. A method for preserving an oxygen infusion comprising an aqueous suspension of molecular assemblies which contain hemoglobin or a heme compound, said method comprising the steps of:
a) modifying the molecular assemblies with polyoxyethylene; and
b) converting the hemoglobin or the heme compound into a deoxy-form by removing oxygen from the suspension.
2. The method of claim 1 , wherein the molecular assemblies are selected from the group consisting of cell membranes, hemoglobin vesicle, lipid heme vesicle, lipid heme-triglyceride microsphere and albumin-lipid heme.
3. The method of claim 1 , wherein the removal of oxygen is performed by gas exchange with an inert gas.
4. The method of claim 1 , further comprising:
storing said suspension in an oxygen-impermeable container filled with an inert gas.
5. The method of claim 1 , wherein the suspension contains a physiologically acceptable reducing agent.
6. The method of claim 1 , wherein the heme compound comprises a porphyrin ring having a substituent, said compound having reversible oxygen-binding potential.
7. The method of claim 1 , wherein the molecular assemblies are modified by fixing the polyoxyethylene onto surfaces thereof.
8. The method of claim 7 , wherein said polyoxyethylene has a molecular weight of about 1,000 to 20,000 Daltons.
9. The method of claim 7 , wherein the molecular assemblies comprise lipid and said polyoxyethylene is present in an amount of about 0.01 to 3 mol % with respect to a total amount of lipid exposed on an outer surface of each particle of the molecular assemblies.
10. The method of claim 7 , wherein the polyoxyethylene is fixed into the surface of the molecular assemblies by a hydrophobic moiety of the components of molecular assembly.
11. The method of claim 10 , wherein the hydrophobic moiety comprises at least one amphipathic molecule selected from the group consisting of ethanolamine phospholipid, cholesterol, alkyl-chain-linked glutamic acid and alkyl-chain-linked lysine.
12. The method of claim 11 , wherein the polyoxyethylene is N-(monomethoxypolyoxyethylene carbamyl)distearyl phosphatidyl-ethanolamine.
13. The method of claim 1 , wherein said oxygen infusion exhibits no loss of oxygen transport function after storage at 40° C. for six months.
14. The method of claim 1 , which further comprises after step b), storing said oxygen infusion under nitrogen.
15. The method of claim 14 , wherein said oxygen infusion exhibits no loss of oxygen transport function after storage at 23° C. under nitrogen for one year.
16. A method of producing an oxygen infusion comprising an aqueous suspension of molecular assemblies which contain hemoglobin or a heme compound, said method comprising the steps of:
a) preparing a suspension of the molecular assembly containing the hemoglobin or the heme compound, the molecular assembly being modified with polyoxyethylene;
b) making the hemoglobin or the heme compound into a deoxy-form by removing oxygen from the suspension; and
c) packing the suspension containing the deoxy-form hemoglobin or heme compound, in an oxygen-impermeable container which is filled with an inert gas.
17. An oxygen infusion, comprising a suspension of molecular assemblies comprising hemoglobin or a heme compound, the assemblies being modified with polyoxyethylene; said hemoglobin or heme compound being in a deoxy-form.
18. The oxygen infusion of claim 17 , wherein said molecular assemblies are modified by having said polyoxyethylene fixed onto surfaces thereof.
19. The oxygen infusion of claim 18 , wherein the molecular assemblies comprises lipid and said polyoxyethylene is present in an amount of about 0.01 to 3 mol % with respect to a total amount of lipid exposed on an outer surface of each particle of the molecular assemblies.
20. The oxygen infusion of claim 17 , wherein said polyoxyethylene has a molecular weight of about 1,000 to 20,000 Daltons.
21. The oxygen infusion of claim 17 , wherein the molecular assemblies are cell membranes.
22. The oxygen infusion of claim 17 , wherein the molecular assemblies are hemoglobin vesicles.
23. The oxygen infusion of claim 17 , wherein the molecular assemblies are lipid heme vesicles.
24. The oxygen infusion of claim 17 , wherein the molecular assemblies are lipid heme-triglyceride microspheres.
25. The oxygen infusion of claim 17 , wherein the molecular assemblies are albumin-lipid heme.
26. The oxygen infusion of claim 17 , which is stored in a container.
27. The oxygen infusion of claim 26 , wherein the container is a bottle.
28. The oxygen infusion of claim 26 , which is stored under an inert gas atmosphere.