POST IRRADIATION SHELF-STABLE DUAL PASTE DIRECT INJECTABLE BONE CEMENT PRECURSOR SYSTEMS AND METHODS OF MAKING SAME

• US 20110152195A1
• Filed: 12/16/2010
• Published: 06/23/2011
• Est. Priority Date: 12/18/2009
• Status: Active Grant

• Current Assignee: Howmedica Osteonics Corp. (Stryker Corporation)
• Original Assignee: Howmedica Osteonics Corp. (Stryker Corporation)
• Inventors: Wai, Adrian Sun, Garigapati, Venkat R., O'Mahony, Donal, Murphy, Matthew E., Hess, Brian
• Granted Patent: US 8,481,065 B2
• Time in Patent Office: Days
• US Class Current: 514/16.7
• CPC Class Codes: A61L 24/001 Use of materials characterised by their function or physical properties
• CPC Class Codes: A61L 24/02 containing inorganic materials
• CPC Class Codes: A61L 24/06 obtained by reactions only involving carbon-to-carbon unsaturated bonds A61L24/043, A61L24/046 take precedence
• CPC Class Codes: A61L 2430/02 for reconstruction of bones; weight-bearing implants
• CPC Class Codes: A61L 27/12 Phosphorus-containing materials, e.g. apatite
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders

Abstract

The present invention relates to a bone cement precursor system that is presented in the form of two shelf-stable pastes which have been terminally sterilized and are held in separate containers during product transport and storage. When the product is used during surgery, these pastes inject to a site of application through a static mixing device by the action of applied injection force. When the two pastes are mixed, they start to react to each other while injecting out. The resulting composition is highly biocompatible, osteoconductive, injectable, rapid setting and bioresorbable, and is useful in connection with bone repair procedures, for example, in the craniomaxillofacial, trauma and orthopedic areas.

Claims

1. A bone cement precursor system comprising:

a first container containing an acidic aqueous paste comprising at least one acidic calcium phosphate mineral, at least one synthetic polymer-based paste stabilizing agent, a pH buffering agent and a humectant, and

a second container containing an alkaline non-aqueous paste comprising at least one basic calcium phosphate mineral, at least one paste stabilizing agent, a surfactant and a solvent.

2. The bone cement precursor system of claim 1, wherein said system is shelf-stable post terminal sterilization.

3. The bone cement of claim 2, wherein said terminal sterilization is gamma irradiation.

4. The bone cement precursor system of claim 1, wherein said at least one acidic calcium phosphate mineral for said acidic aqueous paste is selected from the group consisting of monocalcium phosphate monohydrate (MCPM), monocalcium phosphate anhydrous (MCPA), dicalcium phosphate dihydrate (DCPD), dicalcium phosphate anhydrous (DCPA) and mixtures thereof.

5. The bone cement precursor system of claim 4, wherein the mean particle size of said at least one acidic calcium phosphate mineral is between about 1 μ

m to about 90 μ

m.

6. The bone cement precursor system of claim 4, wherein the amount of said acidic calcium phosphate mineral present in said acidic aqueous paste is between about 5% w/w to about 65% w/w based on the total weight of said acidic aqueous paste.

7. The bone cement precursor system of claim 4, wherein said at least one acidic calcium phosphate mineral for said acidic aqueous paste is monocalcium phosphate monohydrate (MCPM) and dicalcium phosphate anhydrous (DCPA).

8. The bone cement precursor system of claim 7, wherein the mean particle size of said monocalcium phosphate monohydrate (MCPM) is about 30 μ

m to about 90 μ

m.

9. The bone cement precursor system of claim 7, wherein the mean particle size of said dicalcium phosphate anhydrous (DCPA) is about 1 μ

m to about 20 μ

m

10. The bone cement precursor system of claim 1, wherein the at least one synthetic polymer-based paste stabilizing agent for said acidic aqueous paste is selected from the group consisting of polyvinyl pyrrolidone (PVP), polyethylene glycol, and mixtures thereof.

11. The bone cement precursor system of claim 10, wherein the amount of said at least one synthetic polymer-based paste stabilizing agent present in said acidic aqueous paste is 1% w/w and about 10% w/w based on the total weight of said acidic aqueous paste.

12. The bone cement precursor system of claim 1, wherein the pH buffering agent for said acidic aqueous paste is selected from the group consisting of citric acid, tartaric acid, salts thereof and mixtures thereof.

13. The bone cement precursor system of claim 12, wherein the amount of said pH buffering agent present in said acidic aqueous paste is between about 5% w/w and about 8% w/w based on the total weight of said acidic aqueous paste.

14. The bone cement precursor system of claim 1, wherein said humectant for said acidic aqueous paste is selected from the group consisting of glycerol, propylene glycol and mixtures thereof.

15. The bone cement precursor system of claim 14, wherein the amount of said humectant present in said acidic aqueous paste is between about 0.5% w/w and about 2% w/w based on the total weight of said acidic aqueous paste.

16. The bone cement precursor system of claim 1, wherein the amount of said water present in said acidic aqueous paste is between about 15 w/w % to about 25 w/w % based on the total weight of said acidic aqueous paste.

17. The bone cement precursor system of claim 1, wherein said one basic calcium phosphate mineral for said alkaline non-aqueous paste is selected from the group consisting of β

-tricalcium phosphate (β

-TCP), α

-tricalcium phosphate (α

-TCP), tetracalcium phosphate (TTCP), oxyapatite, hydroxyapatite, calcium-deficient hydroxyapatite and mixtures thereof.

18. The bone cement precursor system of claim 17, wherein the mean particle size of said at least one basic calcium phosphate mineral is between about 10 μ

m to about 60 μ

m.

19. The bone cement precursor system of claim 17, wherein the amount of said at least one basic calcium phosphate present in said alkaline non-aqueous paste is between about 10 w/w % to about 80 w/w % based on the total weight of said alkaline non-aqueous paste.

20. The bone cement precursor system of claim 17, wherein said one basic calcium phosphate mineral for said alkaline non-aqueous paste is tetracalcium phosphate (TTCP).

21. The bone cement precursor system of claim 1, wherein said alkaline non-aqueous paste comprises a bimodal mean particle size distribution of said at least one basic calcium phosphate mineral.

22. The bone cement precursor system of claim 21, wherein the mean particle size of a first set of said at least one basic calcium phosphate mineral is between about 10 μ

m to about 30 μ

m, and the mean particle size of a second set of said at least one basic calcium phosphate mineral is between about 25 μ

m to about 60 μ

m.

23. The bone cement precursor system of claim 1, wherein said at least one paste stabilizing agent for said alkaline non-aqueous paste is a natural polymer, synthetic polymer or mixtures thereof.

24. The bone cement precursor system of claim 23, wherein the amount of said synthetic polymer present in said alkaline non-aqueous paste is between about 1 w/w % to about 5 w/w % based on the total weight of said alkaline non-aqueous paste.

25. The bone cement precursor system of claim 23, wherein said synthetic polymer is polyethylene glycol (PEG).

26. The bone cement precursor system of claim 23, wherein the amount of said natural polymer present in said alkaline non-aqueous paste is between about 0 w/w % to about 0.5 w/w % based on the total weight of said alkaline non-aqueous paste.

27. The bone cement precursor system of claim 23, wherein when said at least one paste stabilizing agent for said alkaline non-aqueous paste is said natural polymer, said alkaline non-aqueous paste further comprises an antioxidant.

28. The bone cement precursor system of claim 27, wherein said antioxidant is thioglycerol.

29. The bone cement precursor system of claim 1, wherein said surfactant for said alkaline non-aqueous paste is selected from the group consisting of glycerol monostearate, lecithin, phospholipids, glycerol distearate, polyethylene glycol distearate, block copolymer of PEG-PPG-PEG, block copolymer of PPG-PEG-PPG, polysorbate 80, Span, any polysorbate fatty acid ester, sorbitol ester, and mixtures thereof.

30. The bone cement precursor system of claim 29, wherein the amount of said surfactant present in said alkaline non-aqueous paste is between about 0.5 w/w % to about 2 w/w % based on the total weight of said alkaline non-aqueous paste.

31. The bone cement precursor system of claim 1, wherein said solvent for said alkaline non-aqueous paste is glycerol, thioglycerol, ethanol, propanol, propylene glycol and mixtures thereof.

32. The bone cement precursor system of claim 31, wherein the amount of said solvent present in said alkaline non-aqueous paste is between about 22 w/w % to about 28 w/w % based on the total weight of said alkaline non-aqueous paste.

33. The bone cement precursor system of claim 1, wherein said acidic aqueous paste comprises monocalcium phosphate monohydrate (MCPM) and dicalcium phosphate anhydrous (DCPA), citric acid, water, glycerol, polyvinyl pyrrolidone (PVP) and polyethylene glycol (PEG).

34. The bone cement precursor system of claim 1, wherein said alkaline non-aqueous paste comprises tetracalcium phosphate (TTC), polyethylene glycol (PEG), polysorbate 80, and propylene glycol.

35. The bone cement precursor system of claim 1, wherein said system further comprises an additive.

36. The bone cement precursor system of claim 35, wherein said additive is selected from the group consisting of a protein, osteoinductive material, osteoconductive material, x-ray opacifying agent, medicament, supporting or strengthening filler material, crystal growth adjuster, viscosity modifier, pore forming agent, radiopaque filler and mixtures thereof.

37. A calcium phosphate composition produced by mixing said acidic aqueous paste and said alkaline non-aqueous paste of claim 1.

38. The calcium phosphate composition of claim 37, wherein said calcium phosphate composition is rapid setting.

39. The calcium phosphate composition of claim 37, wherein said calcium phosphate composition is injectable.

40. A device for a dual paste injectable bone cement precursor system comprising:

a syringe body and a static mixing tip,

wherein the syringe body comprises

a first holding chamber containing an acidic aqueous paste comprising at least one acidic calcium phosphate mineral, at least one synthetic polymer-based paste stabilizing agent, a pH buffering agent and a humectant,

a second holding chamber containing an alkaline non-aqueous paste comprising at least one basic calcium phosphate mineral, at least one paste stabilizing agent, a surfactant and a solvent, and

the static mixing tip comprises a structure which allows the two pastes to be blended and to be applied to a desired site.

41. A method of preparing a bone cement comprising:

mixing at least one synthetic polymer based paste stabilizing agent, a pH buffering agent, and water;

adding at least one acidic calcium phosphate mineral to the mixture of said at least one synthetic polymer based paste stabilizing agent, said pH buffering agent and said water to form an acidic aqueous paste;

mixing at least one paste stabilizing agent, a surfactant, and a solvent;

adding at least one basic calcium phosphate mineral to the mixture of said at least one paste stabilizing agent, said surfactant and said solvent to form an alkaline non-aqueous paste;

mixing said acidic aqueous paste with said alkaline non-aqueous paste to form said bone cement.

42. The method of claim 41, further comprising:

storing said acidic aqueous paste in a first container;

storing said alkaline non-aqueous paste in a second container;

providing a device which would inject said acidic aqueous paste and said alkaline non-aqueous paste concurrently from said first container and said second container, respectively, to a static mixing device so that a blended paste of said acidic aqueous paste and said alkaline non-aqueous paste can inject to a site of application by the action of applied injection force.