Methods for making ultrasound contrast agents

• US 9,789,210 B1
• Filed: 03/16/2017
• Issued: 10/17/2017
• 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): Perreira, Melissa J
• Application Number:
  US15/461,469
• Time in Patent Office: 215 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 of ultrasound contrast imaging a subject comprising

(a) activating a phospholipid suspension with a perfluorocarbon gas to form lipid-encapsulated gas microspheres, wherein the phospholipid suspension comprises a phospholipid solution having DPPA, DPPC and MPEG5000-DPPE, in a mole % ratio of 10 to 82 to 8 (10:

82;

8), in propylene glycol, the MPEG5000-DPPE selected as having a calcium concentration of less than 115 parts per million (ppm), and the phospholipid solution having a calcium 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.

4. The method of claim 1, wherein the calcium concentration is determined using atomic absorption spectroscopy.

5. The method of claim 1, wherein the calcium concentration is determined using inductively coupled plasma mass spectrometry (ICP-MS).

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

2. A method of ultrasound contrast imaging a subject comprising

(a) activating a phospholipid suspension with a perfluorocarbon gas to form lipid-encapsulated gas microspheres, wherein the phospholipid suspension comprises a phospholipid solution made under a methanol and toluene free condition and a methyl t-butyl ether free condition and having DPPA, DPPC and MPEG5000-DPPE, in a mole % ratio of 10 to 82 to 8 (10:

82;

8), in propylene glycol, the MPEG5000-DPPE having a calcium concentration of less than 115 parts per million (ppm), and the phospholipid solution having a calcium 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.

3. The method of claim 2, wherein the calcium concentration is determined using atomic absorption spectroscopy.

6. The method of claim 2, wherein the calcium concentration is determined using inductively coupled plasma-mass spectrometry (ICP-MS).

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

9. The method of claim 2, wherein MPEG5000-DPPE is selected as having a calcium concentration of less than 115 ppm.