METHOD FOR THE SYNTHESIS OF HOLLOW SPHERES

• US 20110020236A1
• Filed: 03/13/2009
• Published: 01/27/2011
• Est. Priority Date: 03/19/2008
• Status: Abandoned Application

• Current Assignee: Koninklijke Philips Electronics N.V. (Koninklijke Philips N.V.)
• Original Assignee: Koninklijke Philips Electronics N.V. (Koninklijke Philips N.V.)
• Inventors: Bohmer, Marcel Rene, Hall, Christopher Stephen, Shi, William Tao, Chlon, Caecilia Hendrina Theodora
• Application Number:
  US12/933,126
• Publication Number:
  US 20110020236A1
• Time in Patent Office: Days
• US Class Current: 424/9.3
• CPC Class Codes: A61K 41/0028 Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
• CPC Class Codes: A61K 49/0002 General or multifunctional contrast agents, e.g. chelated agents
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5192 Processes
• CPC Class Codes: B01J 13/125 by evaporation of the solvent apparatus therefor B01J13/043

Abstract

The present invention relates to a method of synthesizing acoustically active biodegradable hollow spheres with a size below 1 micron. By using water soluble organic solvents and pegylated polymers, direct precipitation of these spheres is facilitated leading to a fast and convenient preparation route.

Claims

1. A method for synthesis of a hollow sphere with a polymeric shell comprising the following steps:

providing a solution comprising;

a first polymer (1) with a hydrophilic and a hydrophobic block,

a second polymer (2) not miscible with water

a hydrophobic compound,

a water miscible organic solvent,

mixing the solution with an aqueous solution resulting in a mixture

removal of the water miscible organic solvent from the mixture

lyophilizing to remove the hydrophobic compound from the mixture

2. A method according to claim 1, wherein the hydrophilic organic solvent is selected from the group comprising acetone, tetrahydrofurane, dimethylsulfoxide, dimethylformamide, acetonitrile, glycol ethers and dimethylacetamide, or any combination thereof.

3. A method according to any of claim 1, wherein the first polymer is (1) is selected from the group comprising polylactide, polycaprolactone, polycyanoacrylate and copolymers of one of the foregoing, copolymers of polyglycolide, or any combination thereof.

4. A method according to claim 1 wherein the second polymer (2) comprises an alkyl or a fluorinated end group.

5. A method according to claim 1 wherein the mixture comprises a hydrophobic compound that remains after step (d) and a pharmaceutical or diagnostic compound.

6. A method according to claim 5 wherein the remaining hydrophobic compound is selected from the group comprising alkanes with at least 16 carbon atoms, lipids, paraffin or oils.

7. A hollow sphere with a polymeric shell synthesized according to claim 1.

8. A hollow sphere according to claim 7 with a size from 50 to 400 nm.

9. A hollow sphere according to claim 7 that is able to release the gaseous content upon application of ultrasound.

10. A hollow sphere according to claim 7 wherein the gaseous content is at least partially replaced by a gas pre-cursor.

11. A hollow sphere according to claim 7 wherein the polymeric shell of the sphere includes a targeting moiety.

12. A hollow sphere according to claim 7 wherein the sphere comprises a pharmaceutically active molecule.

13. A hollow sphere according to claim 7 comprising an imaging agent selected from the group consisting of PET, SPECT or MRI agents

14. Use of hollow spheres obtained by the method of claim 1 in ultrasound imaging or ultrasound triggered drug delivery.