Freeze-dried product and gas-filled microvesicles suspension

Patent metadata

Field	Value
Publication number	US-2023414517-A1
Application number	US-202318214060-A
Country	US
Kind code	A1
Filing date	Jun 26, 2023
Priority date	May 15, 2019
Publication date	Dec 28, 2023
Grant date	—

Abstract

A method of manufacturing a suspension of gas-filled microvesicles by reconstituting a freeze-dried product and a suspension obtained according to said method, where the freeze-dried product has been subjected to a thermal treatment

First claim

1 . A method of manufacturing a freeze-dried composition suitable for the preparation of a suspension of stabilized gas-filled microbubbles, said composition comprising: (i) an amphiphilic material; and (ii) a freeze-drying protecting component; which comprises:
a. preparing a liquid mixture comprising said amphiphilic material and said freeze-drying protecting component in a solvent; b. freeze-drying the liquid mixture to remove said solvent and obtain a freeze-dried product; and c. after completion of the freeze-drying of step b, heating said freeze-dried product.

2 . The method according to claim 1 wherein said liquid mixture comprises said amphiphilic material and said freeze-drying protecting component dispersed in an organic solvent.

3 . The method according to claim 1 wherein said liquid mixture comprises said amphiphilic material and said freeze-drying protecting component dispersed in an aqueous emulsion of a water immiscible solvent and water.

4 . The method according to claim 1 wherein said heating step is carried out at a temperature higher than 35° C.

5 . The method according to claim 1 wherein said heating step is carried out at a temperature of 38° C. or higher.

6 . The method according to claim 1 wherein said heating step is carried out at a temperature of 40° C. or higher.

7 . The method according to claim 1 wherein said amphiphilic material comprises a phospholipid.

8 . The method according to claim 7 wherein said amphiphilic material further comprises a fatty acid.

9 . The method according to claim 8 , wherein said amphiphilic material comprises DSPC, DPPG and palmitic acid.

10 . The method according to claim 8 , wherein said amphiphilic material comprises DSPC, DPPE-PEG5000 and palmitic acid.

11 . The method according to any of the preceding claims wherein said freeze-drying protecting component is polyethyleneglycol.

12 . The method according to claim 11 , wherein said freeze-drying protecting component is PEG4000.

13 . The method according to claim 9 , wherein said heating step is carried out at a temperature of from 40° C. to 48° C. for at least 8 hours

14 . The method according to claim 10 , wherein said heating step is carried out at a temperature of 36° C. to 45° C.

15 . The method according to any of the preceding claims, wherein said heating in step c is performed for at least eight hours.

16 . The method according to claim 15 , wherein said heating in step c is performed for at least twelve hours.

17 . The method according to any of the preceding claims wherein said heating in step c is performed at ambient pressure.

18 . A freeze-dried product obtained according to the method of any of the preceding claims 1 to 17 .

19 . A method of manufacturing a suspension of gas-filled microvesicles which comprises reconstituting a freeze-dried product obtained according to the method of any of claims 1 to 17 with a pharmaceutically acceptable liquid carrier in the presence of a physiologically acceptable gas under gentle agitation.

20 . A suspension of gas-filled microvesicles obtained according to the method of manufacturing of claim 19 .

21 . A method of diagnosing which comprises
(i) administering to a patient a suspension of gas-filled microvesicles according to claim 20 ; and (ii) detecting an ultrasound signal from a region of interest in said patient.

22 . A method according to claim 21 which comprises ultrasound imaging of the heart.

23 . A method according to claim 21 which comprises ultrasound imaging of the liver.

24 . A method according to claim 21 which comprises ultrasound imaging of a urinary tract.

Assignees

• Bracco Suisse Sa

Inventors

• Bussat Philippe
• Lassus Anne
• Brochot Jean
• Schneider Michel
• Yan Feng

Classifications

• A61K9/19 Primary

  lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)} · 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

• A61K9/1277

  Preparation processes; Proliposomes · CPC title

• A61K49/223 Primary

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

• A61K9/10

  Dispersions; Emulsions · CPC title