Methods for making ultrasound contrast agents

Patent metadata

Field	Value
Publication number	US-9913919-B2
Application number	US-201715602580-A
Country	US
Kind code	B2
Filing date	May 23, 2017
Priority date	Jul 6, 2016
Publication date	Mar 13, 2018
Grant date	Mar 13, 2018

Abstract

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

First claim

What is claimed is:

1. A method for preparing lipid-encapsulated gas microspheres 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,
combining the phospholipid solution with an aqueous solution to form a phospholipid suspension, and
activating the phospholipid suspension with a perfluorocarbon gas to form lipid-encapsulated gas microspheres.

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 2 , 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 1 , 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. A method for preparing lipid-encapsulated gas microspheres 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,
combining the phospholipid solution with an aqueous solution to form a phospholipid suspension, and
activating the phospholipid suspension with a perfluorocarbon gas, to form lipid-encapsulated gas microspheres.

6. The method of claim 5 , wherein DPPA, DPPC and MPEG-5000-DPPE are present in a mole % ratio of 10 to 82 to 8 (10:82:8).

7. The method of claim 6 , 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.

8. The method of claim 5 , 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.

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

• A61K9/1277

  Preparation processes; Proliposomes · CPC title

• A61K49/223 Primary

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

• A61K49/226

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

• A61K49/227 Primary

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

• A61K9/1271

  Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911}) · CPC title