Preparation of a lipid blend and a phospholipid suspension containing the lipid blend

• US 8,747,892 B2
• Filed: 07/25/2013
• Issued: 06/10/2014
• Est. Priority Date: 01/14/1998
• Status: Expired due to Fees

• Current Assignee: Lantheus Medical Imaging, Inc. (Lantheus Holdings, Inc.)
• Original Assignee: Lantheus Medical Imaging, Inc. (Lantheus Holdings, Inc.)
• Inventors: Hui, Poh K., Bishop, John E., Madrigal, Eleodoro S. Jr.
• Primary Examiner(s): KISHORE, GOLLAMUDI S
• Application Number:
  US13/950,348
• Publication Number:
  US 20130309175A1
• Time in Patent Office: 320 Days
• Field of Search: 424/450, 264/4.1, 264/4.3
• US Class Current: 424/450
• CPC Class Codes: A61B 8/00 Diagnosis using ultrasonic, sonic or infrasonic waves imaging of objects using sonar G01S15/00
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/24 containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• CPC Class Codes: A61K 49/226 Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels
• CPC Class Codes: A61K 49/227 Liposomes, lipoprotein vesicles, e.g. LDL or HDL lipoproteins, micelles, e.g. phospholipidic or polymeric
• CPC Class Codes: A61K 9/1277 Processes for preparing; Proliposomes

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.

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-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.