Granted Patent B2

US 8,747,892 · App. 13/950,348 · Granted Jun 10, 2014

Abstract

Claims (53)

1. A process for preparing a lipid suspension for use with a perfluorocarbon gas as an ultrasound contrast agent, the method comprising:

(a) contacting phospholipids with a first non-aqueous solvent which causes the phospholipids to dissolve and form a lipid solution, wherein the contacting comprises the sequential addition of individual phospholipids to the first non-aqueous solvent wherein the phospholipids are 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC), 1,2-dipalmitoyl-sn-glycero-3-phosphatidic acid, mono sodium salt (DPPA) and N-(methoxypolyethylene glycol 5000 carbamoyl)-1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine, mono sodium salt (MPEG5000-DPPE), or combining said phospholipids with each other prior to their addition to the first non-aqueous solvent;

(b) contacting the non-aqueous lipid solution of (a) with a second non-aqueous solvent which causes the phospholipids to precipitate out as a solid lipid blend;

(c) collecting the solid lipid blend;

(d) contacting the solid lipid blend with a third non-aqueous solvent which causes the lipid blend to dissolve to form a lipid blend solution;

(e) contacting the lipid blend solution with an aqueous solution to yield the lipid suspension; and

(f) filtering the lipid suspension through one or two sterilizing filters to form a filtered lipid suspension.

2. The process of claim 1 , wherein the one or two sterilizing filters are 0.2 micron filters.

3. The process of claim 1 , further comprising dispensing the filtered lipid suspension into a vial.

4. The process of claim 3 , further comprising exchanging the headspace gas of the vial with the perfluorocarbon gas.

5. The process of claim 4 , wherein the perfluorocarbon gas is perfluoropropane.

6. The process of claim 4 , further comprising sterilizing the vial.

7. The process of claim 6 , wherein the vial is sterilized at about 126-130° C. for 1 to 10 minutes.

8. The process of claim 1 , wherein

(i) the first non-aqueous solvent is a mixture of methanol and toluene;

(ii) the second non-aqueous solvent is methyl t-butyl ether;

(iii) the third non-aqueous solvent is propylene glycol;

(iv) the aqueous solution comprises sodium chloride, glycerin, and propylene glycol.

9. The process of claim 8 , wherein

(i) the third non-aqueous solvent is heated to a temperature of about 50-60° C. prior to contacting with the solid lipid blend;

(ii) the aqueous solution is heated to a temperature of about 45-60° C. prior to contacting with the lipid blend solution.

10. The process of claim 3 , wherein

(i) the first non-aqueous solvent is a mixture of methanol and toluene;

(ii) the second non-aqueous solvent is methyl t-butyl ether;

(iii) the third non-aqueous solvent is propylene glycol;

(iv) the aqueous solution comprises sodium chloride, glycerin, and propylene glycol.

11. The process of claim 10 , wherein

(i) the third non-aqueous solvent is heated to a temperature of about 50-60° C. prior to contacting with the solid lipid blend;

(ii) the aqueous solution is heated to a temperature of about 45-60° C. prior to contacting with the lipid blend solution.

12. The process of claim 4 , wherein

(i) the first non-aqueous solvent is a mixture of methanol and toluene;

(ii) the second non-aqueous solvent is methyl t-butyl ether;

(iii) the third non-aqueous solvent is propylene glycol;

(iv) the aqueous solution comprises sodium chloride, glycerin, and propylene glycol.

13. The process of claim 12 , wherein

(i) the third non-aqueous solvent is heated to a temperature of about 50-60° C. prior to contacting with the solid lipid blend;

(ii) the aqueous solution is heated to a temperature of about 45-60° C. prior to contacting with the lipid blend solution.

14. The process of claim 5 , wherein

(i) the first non-aqueous solvent is a mixture of methanol and toluene;

(ii) the second non-aqueous solvent is methyl t-butyl ether;

(iii) the third non-aqueous solvent is propylene glycol;

(iv) the aqueous solution comprises sodium chloride, glycerin, and propylene glycol.

15. The process of claim 14 , wherein

(i) the third non-aqueous solvent is heated to a temperature of about 50-60° C. prior to contacting with the solid lipid blend;

(ii) the aqueous solution is heated to a temperature of about 45-60° C. prior to contacting with the lipid blend solution.

16. The process of claim 6 , wherein

(i) the first non-aqueous solvent is a mixture of methanol and toluene;

(ii) the second non-aqueous solvent is methyl t-butyl ether;

(iii) the third non-aqueous solvent is propylene glycol;

(iv) the aqueous solution comprises sodium chloride, glycerin, and propylene glycol.

17. The process of claim 16 , wherein

(i) the third non-aqueous solvent is heated to a temperature of about 50-60° C. prior to contacting with the solid lipid blend;

(ii) the aqueous solution is heated to a temperature of about 45-60° C. prior to contacting with the lipid blend solution.

Assignments (10)