Methods for making ultrasound contrast agents

Patent metadata

Field	Value
Publication number	US-10583208-B2
Application number	US-201916264176-A
Country	US
Kind code	B2
Filing date	Jan 31, 2019
Priority date	Jul 6, 2016
Publication date	Mar 10, 2020
Grant date	Mar 10, 2020

Abstract

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

First claim

What is claimed is:

1. A method of ultrasound contrast imaging a subject comprising
(a) combining an aqueous solvent with a phospholipid solution to form a phospholipid suspension, and activating the phospholipid suspension with a perfluorocarbon gas to form lipid-encapsulated gas microspheres, wherein the phospholipid solution comprises DPPA, DPPC, MPEG5000-DPPE, and propylene glycol, the MPEG5000-DPPE selected as having a combined calcium and magnesium concentration of less than 115 parts per million (ppm), and the phospholipid solution having a combined calcium and magnesium concentration of less than 0.7 ppm,
(b) administering the lipid-encapsulated gas microspheres to a subject, and
(c) obtaining an ultrasound image of the subject.

2. The method of claim 1 , wherein DPPA, DPPC and MPEG5000-DPPE are present in molar percentages of 5-15%, 77-90% and 5-15%, respectively.

3. The method of claim 1 , wherein DPPA, DPPC and MPEG5000-DPPE are present in a % mole ratio of about 10 to 82 to 8.

4. The method of claim 1 , wherein the perfluorocarbon gas is perfluoropropane gas.

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

6. The method of claim 1 , wherein the phospholipid solution comprises DPPA, DPPC, MPEG5000-DPPE and propylene glycol, and the aqueous solvent comprises water, propylene glycol and glycerol, and wherein the phospholipid suspension comprises DPPA, DPPC, MPEG5000-DPPE, propylene glycol, water and glycerol.

7. The method of claim 6 , wherein water, glycerol and propylene glycol are present in a ratio of about 8:1:1 in the phospholipid suspension.

8. The method of claim 6 , wherein the aqueous solvent further comprises one or more salts.

9. The method of claim 6 , wherein the aqueous solvent further comprises one or more buffers.

10. A method of ultrasound contrast imaging a subject comprising
(a) combining an aqueous solvent with a phospholipid solution to form a phospholipid suspension, and activating the phospholipid suspension with a perfluorocarbon gas to form lipid-encapsulated gas microspheres, wherein the phospholipid suspension is formed under a methanol and toluene free condition and a methyl-t-butyl ether free condition, the phospholipid solution comprises DPPA, DPPC, MPEG5000-DPPE, and propylene glycol, the MPEG5000-DPPE having a combined calcium and magnesium concentration of less than 115 parts per million (ppm), and the phospholipid solution having a combined calcium and magnesium concentration of less than 0.7 ppm,
(b) administering the lipid-encapsulated gas microspheres to a subject, and
(c) obtaining an ultrasound image of the subject.

11. The method of claim 10 , wherein DPPA, DPPC and MPEG5000-DPPE are present in molar percentages of about 5-15%, 77-90% and 5-15%, respectively.

12. The method of claim 10 , wherein DPPA, DPPC and MPEG5000-DPPE are present in a % mole ratio of about 10 to 82 to 8.

13. The method of claim 10 , wherein the perfluorocarbon gas is perfluoropropane gas.

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

15. The method of claim 10 , wherein the phospholipid solution comprises DPPA, DPPC, MPEG5000-DPPE and propylene glycol, and the aqueous solvent comprises water, propylene glycol and glycerol, and wherein the phospholipid suspension comprises DPPA, DPPC, MPEG5000-DPPE, propylene glycol, water and glycerol.

16. The method of claim 15 , wherein water, glycerol and propylene glycol are present in a ratio of about 8:1:1 in the phospholipid suspension.

17. The method of claim 15 , wherein the aqueous solvent further comprises one or more salts.

18. The method of claim 15 , wherein the aqueous solvent further comprises one or more buffers.

Assignees

• Lantheus Medical Imaging Inc

Inventors

• Robinson Simon P
• Siegler Robert W
• Nguyen Nhung Tuyet
• Onthank David C
• Anklekar Tarakeshwar Vishwanath
• Van Kirk Charles Chester

Classifications

• A61K49/226

  Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels · CPC title

• A61K49/223 Primary

  Microbubbles, hollow microspheres, free gas bubbles, gas microspheres · CPC title

• A61K49/227 Primary

  Liposomes, lipoprotein vesicles, e.g. LDL or HDL lipoproteins, micelles, e.g. phospholipidic or polymeric · CPC title

• C07F9/106

  Adducts, complexes, salts of phosphatides · CPC title

• C07F9/09

  Esters of phosphoric acids · CPC title