Methods for making ultrasound contrast agents

• US 10,220,104 B2
• Filed: 03/29/2018
• Issued: 03/05/2019
• Est. Priority Date: 07/06/2016
• Status: Active Grant

• Current Assignee: Lantheus Medical Imaging, Inc. (Lantheus Holdings, Inc.)
• Original Assignee: Lantheus Medical Imaging, Inc. (Lantheus Holdings, Inc.)
• Inventors: Robinson, Simon P., Siegler, Robert W., Nguyen, Nhung Tuyet, Onthank, David C., Anklekar, Tarakeshwar Vishwanath, Van Kirk, Charles Chester
• Primary Examiner(s): Hartley, Michael G.
• Assistant Examiner(s): Lamberski, Jennifer
• Application Number:
  US15/940,932
• Publication Number:
  US 20180221516A1
• Time in Patent Office: 341 Days
• Field of Search: None
• CPC Class Codes: A61B 8/481 involving the use of contrast agent, e.g. microbubbles introduced into the bloodstream analysis of echo signal exploiting properties of a contrast enhancer in devices for short-range imaging with acoustic waves G01S7/52039
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• 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 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: A61K 9/1277 Processes for preparing; Proliposomes
• CPC Class Codes: C07F 9/09 Esters of phosphoric acids
• CPC Class Codes: C07F 9/106 Adducts, complexes, salts of phosphatides

Abstract

Provided herein are improved methods for preparing phospholipid formulations including phospholipid UCA formulations.

Claims

1. A method for preparing a phospholipid suspension useful for preparing an ultrasound contrast agent comprising

combining DPPA, DPPC and MPEG5000-DPPE, in propylene glycol to form a phospholipid solution, the MPEG5000-DPPE selected as having a calcium concentration of less than 115 parts per million (ppm), wherein the phospholipid solution has a calcium concentration of less than 0.7 ppm, and

combining the phospholipid solution with an aqueous solution to form a phospholipid suspension.

2. The method of claim 1, wherein DPPA, DPPC and MPEG-5000-DPPE are present in a mole % ratio of 10 to 82 to 8 (10:

82;

8).

3. The method of claim 1, wherein calcium concentration of DPPA is less than 780 ppm, calcium concentration of DPPC is less than 90 ppm, and the calcium concentration of propylene glycol is less than 0.7 ppm.

4. The method of claim 2, wherein calcium concentration of DPPA is less than 780 ppm, calcium concentration of DPPC is less than 90 ppm, and calcium concentration of propylene glycol is less than 0.7 ppm.

5. The method of claim 1, further comprising placing the phospholipid suspension in a container.

6. The method of claim 5, further comprising introducing a perfluorocarbon gas into the container.

7. The method of claim 5, wherein the container comprises perfluorocarbon gas.

8. The method of claim 6, wherein the perfluorocarbon gas is perfluoropropane gas.

9. The method of claim 7, wherein the perfluorocarbon gas is perfluoropropane gas.

10. A method for preparing a phospholipid suspension useful for preparing an ultrasound contrast agent comprising

combining DPPA, DPPC and MPEG5000-DPPE in propylene glycol, in a methanol and toluene free and methyl t-butyl ether free condition, to form a phospholipid solution, wherein MPEG5000-DPPE has a calcium concentration of less than 115 parts per million (ppm), and wherein the phospholipid solution has a calcium concentration of less than 0.7 ppm, and

combining the phospholipid solution with an aqueous solution to form a phospholipid suspension.

11. The method of claim 10, wherein DPPA, DPPC and MPEG-5000-DPPE are present in a mole % ratio of 10 to 82 to 8 (10:

82;

8).

12. The method of claim 10, wherein calcium concentration of DPPA is less than 780 ppm, calcium concentration of DPPC is less than 90 ppm, and the calcium concentration of propylene glycol is less than 0.7 ppm.

13. The method of claim 11, wherein calcium concentration of DPPA is less than 780 ppm, calcium concentration of DPPC is less than 90 ppm, and calcium concentration of propylene glycol is less than 0.7 ppm.

14. The method of claim 10, further comprising placing the phospholipid suspension in a container.

15. The method of claim 14, further comprising introducing a perfluorocarbon gas into the container.

16. The method of claim 14, wherein the container comprises perfluorocarbon gas.

17. The method of claim 15, wherein the perfluorocarbon gas is perfluoropropane gas.

18. The method of claim 16, wherein the perfluorocarbon gas is perfluoropropane gas.