Lipid-encapsulated gas microsphere compositions and related methods

• US 10,022,460 B2
• Filed: 05/23/2017
• Issued: 07/17/2018
• Est. Priority Date: 12/31/2014
• 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., Onthank, David C., Nguyen, Nhung Tuyet
• Primary Examiner(s): Hartley, Michael G
• Assistant Examiner(s): LAMBERSKI, JENNIFER A
• Application Number:
  US15/602,534
• Publication Number:
  US 20170258946A1
• Time in Patent Office: 420 Days
• Field of Search: None
• 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 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 9/5089 Processes

Abstract

The invention provides, inter alia, improved lipid formulations used to generate lipid-encapsulated gas microspheres, and methods of their use.

Claims

1. A composition of an ultrasound contrast agent comprising

a non-aqueous mixture comprising DPPA, DPPC and MPEG5000-DPPE in propylene glycol and/or glycerol, and

a perfluorocarbon gas,

wherein the non-aqueous mixture comprises less than 5% w/w (weight/weight) water,

and wherein DPPA, DPPC and MPEG5000-DPPE are present in a ratio of about 10:

82;

8 (mole %).

2. The composition of claim 1, wherein the composition comprises less than 10% impurities relative to total lipid content when stored at room temperature for about 3 months.

3. The composition of claim 1, wherein the composition comprises less than 5% impurities relative to total lipid content when stored at room temperature for about 3 months.

4. The composition of claim 1, wherein the composition comprises less than 2% impurities relative to total lipid content when stored at room temperature for about 3 months.

5. The composition of claim 2, wherein the impurities are measured using HPLC.

6. The composition of claim 1, wherein the non-aqueous mixture comprises DPPA, DPPC and MPEG5000-DPPE in propylene glycol.

7. The composition of claim 6, wherein the weight ratio of DPPA, DPPC and MPEG5000-DPPE combined to propylene glycol is in a range of about 1:

100 to about 1;

600.

8. The composition of claim 1, wherein the non-aqueous mixture comprises DPPA, DPPC and MPEG5000-DPPE in propylene glycol and glycerol.

9. The composition of claim 8, wherein the weight ratio of DPPA, DPPC and MPEG5000-DPPE combined to propylene glycol to glycerol is in a range of about 1:

100;

100 to about 1;

600;

700.

10. The composition of claim 1, wherein the non-aqueous mixture comprises DPPA, DPPC and MPEG5000-DPPE in glycerol.

11. The composition of claim 10, wherein the weight ratio of DPPA, DPPC and MPEG5000-DPPE combined to glycerol is about 1:

100 to about 1;

700.

12. The composition of claim 1, wherein the composition further comprises a buffer.

13. The composition of claim 1, wherein the composition further comprises a non-phosphate buffer.

14. The composition of claim 1, wherein DPPA, DPPC and MPEG5000-DPPE combined are present in a concentration of about 0.1 to about 10 mg per ml of non-aqueous mixture.

15. The composition of claim 1, wherein the perfluorocarbon gas is perfluoropropane gas.

16. The composition of claim 1, wherein the composition consists essentially of DPPA, DPPC, MPEG5000-DPPE, propylene glycol, and perfluorocarbon gas.

17. The composition of claim 1, wherein the composition is provided in a vial.

18. The composition of claim 1, wherein the composition is provided in a vial with a V-bottom.

19. The composition of claim 1, wherein the composition is provided in a vial with a flat-bottom.

20. The composition of claim 1, wherein the composition is provided in a vial with a rounded-bottom.

21. The composition of claim 1, wherein the composition is provided in a single chamber container.

22. The composition of claim 1, wherein the composition is provided in a multiple chamber container.

23. A container comprising the composition of claim 1 in a first chamber and an aqueous diluent in a second chamber.

24. The container of claim 23, wherein the aqueous diluent is an aqueous buffered saline solution.