Biphasic calcium phosphate cement for drug delivery

• US 8,529,933 B2
• Filed: 07/26/2010
• Issued: 09/10/2013
• Est. Priority Date: 07/27/2009
• Status: Active Grant

• Current Assignee: Warsaw Orthopedic Incorporated (Medtronic Plc)
• Original Assignee: Warsaw Orthopedic Incorporated (Medtronic Plc)
• Inventors: Amsden, Brian G., Garcia, Monica Y., Grant, Ian D., Scifert, Jeffrey L., Smith, Timothy J. N.
• Primary Examiner(s): Azpuru, Carlos
• Assistant Examiner(s): HAGOPIAN, CASEY SHEA
• Application Number:
  US12/843,357
• Publication Number:
  US 20110021427A1
• Time in Patent Office: 1,142 Days
• Field of Search: None
• US Class Current: 424/423
• CPC Class Codes: A61L 2300/402 Anaestetics, analgesics, e.g. lidocaine
• CPC Class Codes: A61L 2300/404 Biocides, antimicrobial agents, antiseptic agents
• CPC Class Codes: A61L 2300/414 Growth factors
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 24/0015 Medicaments; Biocides
• CPC Class Codes: A61L 24/0042 Materials resorbable by the body
• CPC Class Codes: A61L 24/0063 Phosphorus containing materials, e.g. apatite
• CPC Class Codes: A61L 24/046 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L24/043 takes precedence
• CPC Class Codes: A61L 24/08 Polysaccharides A61L24/043 takes precedence
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/20 Polysaccharides
• CPC Class Codes: A61L 27/46 with phosphorus-containing inorganic fillers
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 27/58 Materials at least partially resorbable by the body
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: C08L 5/02 Dextran; Derivatives thereof
• CPC Class Codes: C08L 71/02 Polyalkylene oxides

Abstract

This invention relates to biomineral-based cements incorporating biopolymer carriers for the site specific introduction of natural or synthetic compounds that influence bone repair and/or patient recovery. The invention further relates to methods for producing such biphasic calcium phosphate cements for drug delivery.

Claims

1. A settable biphasic composition in the form of a flowable paste, comprising:

a plurality of individual calcium phosphate particles wherein the calcium phosphate particles have a portion of the phosphate substituted with silicon;

a liquid capable of supporting calcium phosphate precipitation;

a bioabsorbable polymer at a concentration that enable tissue ingrowth into the composition upon polymer absorption; and

sodium phosphate or potassium phosphate.

2. The settable biphasic composition of claim 1, wherein the composition is a bone cement.

3. The settable biphasic composition of claim 2, wherein the calcium phosphate particles are at least 65% tricalcium phosphate.

4. The settable biphasic composition of claim 1, wherein the bioabsorbable polymer comprises polyethylene glycol or dextran.

5. The settable biphasic composition of claim 4, further comprising one or more therapeutic agents.

6. The settable biphasic composition of claim 5, wherein the therapeutic agent is selected from the group consisting of BMP-2, BMP-7, TGFβ

, GDF-5, and combinations thereof.

7. The settable biphasic composition of claim 5, wherein the therapeutic agent comprises an analgesic or an antimicrobial agent.

8. The settable biphasic composition of claim 1, wherein the bioabsorbable polymer is present at less than 75% by weight of the bioabsorbable polymer and calcium phosphate particles mixture.

9. The settable biphasic composition of claim 1, further comprising potassium phosphate, wherein the bioabsorbable polymer comprises dextran.

10. A method for the production of a calcium phosphate composition, the method comprising:

mixing a silicon-substituted calcium phosphate powder, a biodegradable polymer, and a setting accelerant with a therapeutic agent and an aqueous solution; and

producing a flowable silicon-substituted calcium phosphate paste having a therapeutic agent distributed therein.

11. The method according to claim 10, wherein biodegradable polymer comprises polyethylene glycol (PEG).

12. The method according to claim 10, wherein the setting accelerant comprises sodium phosphate or potassium phosphate at a concentration of between about 0.5% and about 15% by weight.

13. The method according to claim 10, wherein the silicon-substituted calcium phosphate powder is prepared by a process comprising sintering a silicon doped calcium phosphate powder at a temperature between about 1000°

C. and about 1300°

C.

14. The method according to claim 13, wherein the silicon-substituted calcium phosphate powder has up to about 5 weight percent silicon.

15. The method according to claim 14, wherein the silicon-substituted calcium phosphate powder has between about 0.5 and about 2.0 weight percent of silicon.

16. The method according to claim 14, wherein the biodegradable polymer is present at less than 30% by weight of the calcium phosphate composition.

17. The method according to claim 10, wherein the silicon-substituted calcium phosphate powder and biodegradable polymer are mixed together prior to addition of the aqueous solution.

18. A silicon-substituted calcium phosphate cement kit comprising:

silicon-substituted calcium phosphate particles, a biocompatible polymer, and a setting accelerator in a first container;

an aqueous solution in a second container; and

a lyophilized therapeutic agent in a third container, wherein the silicon-substituted calcium phosphate particles, biocompatible polymer and aqueous solution are mixed to form a settable silicon-substituted calcium phosphate paste.

19. The silicon-substituted calcium phosphate cement kit of claim 18, wherein the therapeutic agent comprises BMP-2, BMP-7 or GDF-5.

20. The silicon-substituted calcium phosphate cement kit of claim 19, further comprising a calcium salt selected from the group consisting of calcium chloride, calcium citrate, calcium carbonate, calcium gluconate, calcium phosphate, calcium sulfate and combinations thereof.