Formulation of solid nano-sized particles in a gel-forming system

• US 10,064,960 B2
• Filed: 11/26/2012
• Issued: 09/04/2018
• Est. Priority Date: 11/25/2011
• Status: Active Grant

• Current Assignee: Danmarks Pã¦Dagogiske Universitet
• Original Assignee: Danmarks Pã¦Dagogiske Universitet
• Inventors: Jolck, Rasmus Irming, Albrechtsen, Morten, Bjerg, Lise Norkjaer, Andresen, Thomas Lars
• Primary Examiner(s): Brutus, Joel F
• Application Number:
  US14/360,518
• Publication Number:
  US 20140343413A1
• Time in Patent Office: 2,108 Days
• Field of Search: 600420
• CPC Class Codes: A61B 5/0073 by tomography, i.e. reconstruction of 3D images from 2D projections A61B5/0066 takes precedence
• CPC Class Codes: A61B 6/481 involving the use of contrast agents
• CPC Class Codes: A61B 6/505 for diagnosis of bone
• CPC Class Codes: A61K 49/04 X-ray contrast preparations
• CPC Class Codes: A61K 49/0457 Semi-solid forms, ointments, gels, hydrogels
• CPC Class Codes: A61K 49/0485 Nanoparticles, nanobeads, nanospheres, nanocapsules, i.e. having a size or diameter smaller than 1 micrometer
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

The present invention relates to novel formulations comprising a plurality of nano-sized solid particles and a gel-forming system, useful, e.g. for imaging of the body of a mammal. Also described are kits comprising such formulations and imaging methods utilizing such formulations or kits.

Claims

1. A tissue marker formulation comprising

i) a plurality of solid in-organic particles having a (number) average diameter of 1-500 nm, and

ii) an organic gel-forming system,

wherein the organic gel-forming system undergoes gel-formation when injected into the body of a mammal, and wherein the formulation is imagable,

wherein said plurality of solid in-organic particles comprise, one or more X-ray contrast agents, radioactive compounds, paramagnetic compounds, fluorescent compounds or ferromagnetic compounds, or any mixture thereof, and

wherein the viscosity of the formulation is less than 10,000 centipoise (cP) at 20°

C.

2. The formulation according to claim 1, wherein the imaging is X-ray imaging.

3. The formulation according to claim 1, wherein said plurality of solid in-organic particles comprise one or more X-ray contrast agents.

4. The formulation according to claim 3, wherein the one or more X-ray contrast agents, radioactive compounds, paramagnetic compounds or ferromagnetic compounds are present in metal form, alloy form, or salt form.

5. The formulation according to claim 1, comprising one or more X-ray contrast agents selected from the group consisting of gold (Au), bismuth (Bi), iron (Fe), barium (Ba), calcium (Ca), and magnesium (Mg).

6. The formulation according to claim 5, wherein said plurality of solid in-organic particles comprise gold (Au).

7. The formulation according to claim 1, wherein said plurality of solid in-organic particles are coated with polyethylene glycol (PEG) or poly(N-isopropyl acrylamide (PNIPAM).

8. The formulation according to claim 1, wherein the organic gel-forming system undergoes gel-formation in response to a temperature in the range of 10 to 65°

C.

9. The formulation according to claim 1, wherein the organic gel-forming system undergoes gel-formation in response to a temperature in the range of 35 to 40°

C.

10. The formulation according to claim 1, wherein the organic gel-forming system undergoes gel-formation in response to hydration.

11. The formulation according to claim 1, wherein the organic gel-forming system undergoes gel-formation in response to an ion-concentration in the range of 1 uM to 500 mM.

12. The formulation according to claim 1, wherein the organic gel-forming system undergoes gel-formation in response to an ion concentration in the range 1 mM to 200 mM.

13. The formulation according to claim 1, wherein the organic gel-forming system undergoes gel-formation in response to a pH in the range of 6 to 8.

14. The formulation according to claim 1, wherein the organic gel-forming system undergoes gel-formation in response to a pH in the range of 6 to 8 and a temperature in the range of 35 to 40°

C.

15. The formulation according to claim 1, wherein the organic gel-forming system undergoes gel-formation in response to contacting with an initiator.

16. The formulation according to claim 1, wherein the organic gel-forming system comprises poly(ethylene glycol-b-caprolactone) (PEG-PCl).

17. The formulation according to claim 1, wherein the organic gel-forming system comprises sucrose acetate isobutyrate (SAIB).

18. The formulation according to claim 17, wherein the organic gel-forming system further comprises poly(D,L-lactic acid) and/or poly(lactic-co-glycolic acid) (PGLA).

19. The formulation according to claim 1, wherein the organic gel-forming system comprises alginate and chitosan.

20. The formulation according to claim 1, wherein the organic gel-forming system comprises one or more polymers, lipids, peptides or any combination thereof.

21. The formulation according to claim 1, wherein the plurality of solid in-organic particles constitute 0.001-50% by weight of the formulation.

22. The formulation according to claim 1, wherein the formulation is a tissue sealant.

23. A kit comprising a syringe, a hypodermal needle adapted to an open end of said syringe, and a formulation according to claim 1.

24. The kit according to claim 23, wherein said formulation is held in the interior of said syringe.

25. The kit according to claim 23, which has a shelf-life of at least 6 months.

26. The formulation according to claim 1, wherein the formulation is parenterally administered to a predetermined location of the body of said mammal, and wherein an X-ray image of at least a part of the body of the mammal including the predetermined location is recorded.