Targeted gas-filled microvesicles formulation

Patent metadata

Field	Value
Publication number	US-12070512-B2
Application number	US-202117352773-A
Country	US
Kind code	B2
Filing date	Jun 21, 2021
Priority date	Dec 18, 2014
Publication date	Aug 27, 2024
Grant date	Aug 27, 2024

Abstract

Suspension of gas-filled microvesicles comprising a targeting ligand for binding to KDR or VEGF/KDR complex.The suspension is obtained by reconstituting a freeze-dried residue with a carbohydrate-containing solution in the presence of a physiologically acceptable gas and is stabilized by the presence of histidine.

First claim

The invention claimed is:

1. An aqueous suspension of gas-filled microvesicles, said gas-filled microvesicles comprising distearoyl-phosphatidyl-choline (DSPC), palmitic acid, DPPE-PEG5000, and a targeting ligand comprising a peptide having an amino acid sequence selected from AGPTWCEDDWYYCWLFGTGGGK (SEQ ID NO: 01), VCWEDSWGGEVCFRYDPGGGK (SEQ ID NO: 02) or a combination thereof, said aqueous suspension further comprising a carbohydrate and a histidine at a concentration of from 1.5 mM to 20 mM such that the aqueous suspension is compatible with intravenous injection.

2. The aqueous suspension according to claim 1 wherein said targeting ligand is in a form of a dimeric peptide comprising a combination of SEQ ID NO: 01 and SEQ ID NO: 02.

3. The aqueous suspension according to claim 1 , wherein said carbohydrate is a glucose.

4. The aqueous suspension according to claim 1 , wherein the palmitic acid is present in a molar amount of from 5% to 20%.

5. The aqueous suspension according to claim 1 , wherein the peptide is conjugated with a phospholipid to form a lipopeptide.

6. The aqueous suspension according to claim 5 , wherein said lipopeptide is present in a molar amount of from 0.1% to 5% by molar ratio with respect to other components of the gas-filled microvesicles.

7. The aqueous suspension according to claim 1 , wherein said targeting ligand is a lipopeptide of formula II:

8. The aqueous suspension according to claim 1 , wherein said gas-filled microvesicles comprise a fluorinated physiologically acceptable gas.

9. The aqueous suspension according to claim 1 , wherein the concentration of the histidine in the aqueous suspension is from 2.5 mM to 10 mM.

10. A pharmaceutical kit for preparing an injectable aqueous suspension of gas-filled microvesicles comprising:
a first container comprising a physiologically acceptable gas in contact with a freeze-dried formulation comprising (i) distearoyl-phosphatidyl-choline (DSPC), palmitic acid, DPPE-PEG5000, (ii) a targeting ligand comprising a peptide having an amino acid sequence selected from AGPTWCEDDWYYCWLFGTGGGK (SEQ ID NO: 01), VCWEDSWGGEVCFRYDPGGGK (SEQ ID NO: 02) or a combination thereof, and (iii) a histidine; and
a second container comprising a carbohydrate-containing aqueous solution capable of reconstituting the freeze-dried formulation into the injectable aqueous suspension of gas-filled microvesicles such that the concentration of the histidine in the injectable aqueous suspension of gas-filled microvesicles is from 1.5 mM to 20 mM.

11. The pharmaceutical kit according to claim 10 , wherein said targeting ligand is in a form of a dimeric peptide comprising a combination of SEQ ID NO: 01 and SEQ ID NO: 02.

12. The pharmaceutical kit according to claim 10 , wherein the concentration of the histidine in the injectable aqueous suspension of gas-filled microvesicles is from 2.5 mM to 10 mM.

13. A method of using the pharmaceutical kit according to claim 10 for imaging a region of interest in a subject comprising:
preparing an aqueous suspension of gas-filled microvesicles by combining contents of the first container with the carbohydrate-containing aqueous solution such that the concentration of histidine in the aqueous suspension of gas-filled microvesicles is from 1.5 mM to 20 mM;
administering an effective amount of the aqueous suspension of gas-filled microvesicles to the subject by intravenous injection;
submitting said region of interest to ultrasound irradiation, and
collecting respective echo signals from said region of interest.

14. The pharmaceutical kit according to claim 10 , wherein said carbohydrate is a glucose.

15. The pharmaceutical kit according to claim 10 , wherein the peptide is conjugated with a phospholipid to form a lipopeptide.

16. The pharmaceutical kit according to claim 10 , wherein said targeting ligand is a lipopeptide of formula II:

17. The pharmaceutical kit according to claim 10 , wherein the physiologically acceptable gas is a fluorinated physiologically acceptable gas.

Assignees

• Bracco Suisse Sa

Inventors

• Bussat Philippe
• Lassus Anne

Classifications

• A61B8/481 Primary

  involving the use of contrast agents, e.g. microbubbles introduced into the bloodstream · CPC title

• 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