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Last Updated: March 29, 2024

Details for Patent: 8,084,056


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Title:Preparation of a lipid blend and a phospholipid suspension containing the lipid blend
Abstract: The present invention describes processes for the preparation of a lipid blend and a uniform filterable phospholipid suspension containing the lipid blend, such suspension being useful as an ultrasound contrast agent.
Inventor(s): Hui; Poh K. (Wellesley, MA), Bishop; John E. (Groton, MA), Madrigal, Jr.; Eleodoro S. (Acton, MA)
Assignee: Lantheus Medical Imaging, Inc. (North Billerica, MA)
Filing Date:Sep 22, 2003
Application Number:10/667,931
Claims: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-phosphotidic 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 a lipid suspension comprising the third non-aqueous solvent.

2. The process of claim 1, wherein each of the phospholipids has a gel to liquid crystalline phase temperature and wherein the lipid blend solution of step (d) is heated to a temperature that is about equal to or above the highest gel to liquid crystalline phase temperature of the phospholipids.

3. The process of claim 1, wherein the first non-aqueous solvent is a mixture of methanol and toluene.

4. The process of claim 1, wherein the second non-aqueous solvent is methyl t-butyl ether.

5. The process of claim 1, wherein the third non-aqueous solvent is selected from propylene glycol, ethylene glycol, and polyethylene glycol 300.

6. The process of claim 5, wherein the third non-aqueous solvent is propylene glycol.

7. The process of claim 1, wherein the aqueous solution contains water, saline, a saline and glycerin mixture, or a saline and glycerin and non-aqueous solvent mixture.

8. The process of claim 7, wherein the aqueous solution contains a saline and glycerin mixture.

9. The process of claim 7, wherein the aqueous solution contains a saline, glycerin, and propylene glycol mixture.

10. The process of claim 1, wherein the first non-aqueous solvent contains a mixture of methanol and toluene and wherein the second non-aqueous solvent is methyl t-butyl ether.

11. The process of claim 1, wherein the third non-aqueous solvent is propylene glycol and wherein the aqueous solution contains a saline, glycerin, and propylene glycol mixture.

12. The process of claim 10, wherein the third non-aqueous solvent is propylene glycol and wherein the aqueous solution contains a saline, glycerin, and propylene glycol mixture.

13. The process according to claim 12, wherein sodium chloride, glycerin, propylene glycol, and about 0.75 to 1.0 mg/mL of the lipid blend are present in the lipid suspension.

14. The process according to claim 1, wherein the third non-aqueous solvent is heated to a temperature of about 30 to 70.degree. C. prior to contacting with the solid lipid blend.

15. The process according to claim 1, wherein the third non-aqueous solvent is heated to a temperature of about 50 to 55.degree. C. prior to contacting with the solid lipid blend.

16. The process according to claim 1, wherein in step (d) the ratio of solid lipid blend to third non-aqueous solvent is from about 5 mg of solid lipid blend per mL of non-aqueous solvent to about 15 mg/mL of solid lipid blend per mL of non-aqueous solvent.

17. The process according to claim 16, wherein the ratio of solid lipid blend to third non-aqueous solvent is about 10 mg/mL.

18. The process according to claim 1, wherein in step (e), the aqueous solution is heated to a temperature of about 45 to 60.degree. C. prior to contacting with the lipid blend solution.

19. The process according to claim 18, wherein the aqueous solution is heated to a temperature of about 50 to 55.degree. C. prior to contacting with the lipid blend solution.

20. The process according to claim 3, wherein the lipid blend solution is heated to a temperature of at least about 67.degree. C.

21. The process according to claim 3, wherein step (d) of the process further comprises: filtering the lipid blend solution through a sterilizing filter to form a filtered lipid blend solution.

22. The process according to claim 21, wherein step (d) of the process further comprises: filtering the filtered lipid blend solution through a second sterilizing filter to form a twice filtered lipid blend solution.

23. The process according to claim 22, wherein the sterilizing filters are at a temperature of from about 70 to 80.degree. C.

24. The process according to claim 23, wherein 0.2 .mu.m hydrophilic filters are used.

25. The process according to claim 21, wherein the process further comprises: dispensing the filtered lipid blend solution into a vial.

26. The process according to claim 25, wherein the process further comprises: exchanging the headspace gas of the vial with a perfluorocarbon gas.

27. The process according to claim 26, wherein the perfluorocarbon gas is perfluoropropane.

28. The process according to claim 26, wherein the process further comprises: sterilizing the vial.

29. The process according to claim 28, wherein the vial is sterilized at about 126-130.degree. C. for 1 to 10 minutes.

30. 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 contains a saline and glycerin and non-aqueous solvent mixture; v) the third non-aqueous solvent is heated to a temperature of about 50-60.degree. C. prior to contacting with the solid lipid blend; vi) in step (d) the ratio of solid lipid blend to third non-aqueous solvent is from about 5 mg of solid lipid blend per mL of non-aqueous solvent to about 15 mg/mL of solid lipid blend per mL of non-aqueous solvent; vii) in step (e), the aqueous solution is heated to a temperature of about 45 to 60.degree. C. prior to contacting with the lipid blend solution; viii) step (d) of the process optionally comprises filtering the lipid blend solution through a sterilizing filter to form a filtered lipid blend solution; ix) the process comprises dispensing the filtered lipid blend solution into a vial; x) wherein the process comprises exchanging the headspace gas of the vial with perfluoropropane; and xi) the process comprises sterilizing the vial.

31. The process according to claim 30, wherein sodium chloride, glycerin, propylene glycol, and about 0.75 to 1.0 mg/mL of the lipid blend are present in the lipid suspension.

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